JP3174189B2 - Immune function suppressant - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an immunosuppressant containing an enopyranose derivative represented by the formula (I) as an active ingredient.

[0002]

2. Description of the Related Art In general, immunosuppressive agents are used in so-called autoimmune hemolytic anemia such as diseases caused by abnormal enhancement of immune function, such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis, and autoimmune hemolytic anemia. It is used for the treatment of immune diseases and for the suppression of rejection during organ transplantation. As conventional immune function inhibitors,
Steroid hormones, azathioprine, cyclophosphamide and the like have been used.

[0003]

However, conventional immunological function inhibitors act not only on immune cells but also non-selectively on a wide range of cells to affect their functions and proliferation. Serious side effects such as granulocytopenia and renal dysfunction have been regarded as problems. Therefore, there is a need for a drug having a strong inhibitory activity on immune function and having as few side effects as possible.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that an enopyranose derivative having a chemical structure completely different from the active ingredient of a conventional immune function inhibitor exhibits an immune function inhibitory action, and have led to the present invention. That is, the present invention provides a compound represented by the general formula (I):

[0005]

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(Wherein R ¹ is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group, an alkynyl group, --OSO
₂ R ⁷ groups, halogen atom, -OCOR ⁷ group, -NHCO
R ⁸ , an alkoxy group, a phenyl group which may be substituted or a sugar derivative residue, R ² is a hydrogen atom or an alkyl group, R ³ is a hydrogen atom or a halogen atom, and R ⁴
Is a hydrogen atom, -COR ⁹ group, an optionally substituted silyl group or an optionally substituted alkyl group, and R ⁵ and R ⁶
Is a hydroxyl group, an optionally substituted alkoxy group, a sugar derivative residue, an optionally substituted cycloalkyloxy group or an -OCOR ¹⁰ group, and the other is a hydrogen atom or an optionally substituted alkyl group. Yes, R ⁴ and R ⁵
May together form a single bond, in which case R ⁶
Is a hydrogen atom or an alkyl group which may be substituted;
⁷ , R ⁹ and R ¹⁰ are each an alkyl group or a phenyl group which may be substituted, R ⁸ is an alkyl group, a phenyl group which may be substituted or a benzyloxy group;
Is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group,
Optionally substituted cycloalkyl group, optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted furanyl group, optionally substituted thienyl group, formyl group, -COR ¹¹ group,- A C (W ¹ ) W ² R ¹¹ group or a mono-SO ₂ R ¹¹ group, wherein R ¹¹ is an optionally substituted chain hydrocarbon group, an optionally substituted monocyclic hydrocarbon group,
An optionally substituted polycyclic hydrocarbon group, an optionally substituted monocyclic heterocyclic group or an optionally substituted polycyclic heterocyclic group, wherein W ¹ is an oxygen atom or a sulfur atom; ² is an oxygen atom, a sulfur atom or a -NH- group, Y is a hydrogen atom,
Which is an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group) or a salt thereof as an active ingredient. Or, it relates to an anti-inflammatory agent.

In the general formula (I), R ¹ , R ² , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , an alkyl group represented by X and Y or an alkyl moiety constituting a functional group include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl , nonyl, decyl, tetradecyl, pentadecyl, octadecyl, and include those of C ₁ -C _20, such as nonadecyl, Moreover, they structural isomers, linear or branched aliphatic. Examples of the alkenyl group represented by R ¹ , X and Y include those having C _{2 to} C ₂₀ such as ethenyl, propenyl and butenyl, and include those having structural isomers of linear or branched aliphatic chains. Examples of the alkynyl group represented by R ¹ , X and Y include C ₂ -C ₂ such as ethynyl, propynyl and butynyl.
₂₀ and also includes those having structural isomers of linear or branched fatty chains.

The halogen atom represented by R ¹ and R ³ in the general formula (I) includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. R ¹ and R ^{5 in the} general formula (I)
And the sugar derivative residue represented by R ⁶ include:

[0009]

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And the like. R ^{5 of} the general formula (I),
Examples of the cycloalkyl moiety of the cycloalkyl group or cycloalkyloxy group represented by R ⁶ and X include C ₃ -C 4 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
There are _eight .

The substituent of the optionally substituted phenyl group represented by R ¹ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ in the formula (I) includes halogen atoms such as fluorine, chlorine, bromine and iodine; Examples include an alkyl group such as methyl and ethyl, and a nitro group.

The substituent of the optionally substituted silyl group represented by R ⁴ in the general formula (I) includes methyl, ethyl,
Examples include alkyl groups such as propyl and butyl, and phenyl groups.

R ¹ , R ⁴ , R ⁵ and R ^{6 of the} general formula (I)
Examples of the substituent of the optionally substituted alkyl group, the optionally substituted alkoxy group or the optionally substituted cycloalkyloxy group include an alkoxy group such as methoxy and ethoxy, a phenyl group, and a hydroxyl group. .

One or more of these substituents may be substituted, and in the case of two or more, they may be the same or different. Further, X and Y in the general formula (I)
In the definition, an alkyl group which may be substituted, an alkenyl group which may be substituted and a substituent of an alkynyl group which may be substituted include fluorine, chlorine, bromine, halogen atoms such as iodine, hydroxyl group, phenyl group, Examples include alkyl-substituted phenyl groups such as toluyl and xylyl, pyridyl groups, furanyl groups, thienyl groups, acetoxy groups, acyloxy groups such as valeroxy groups, azide groups and amino groups. A phenyl group which may be substituted, a pyridyl group which may be substituted, a furanyl group which may be substituted or a thienyl group which may be substituted, such as a halogen atom such as fluorine, chlorine, bromine and iodine; Groups, alkyl groups such as methyl and ethyl, acyloxy groups such as acetoxy and valeroxy, and nitro groups An amino group be mentioned. One or two or more of these substituents may be substituted, and when they are two or more, they may be the same or different.

In the general formula (I), examples of the chain hydrocarbon group contained in R ¹¹ include an alkyl group, an alkenyl group and an alkynyl group. Examples of the monocyclic hydrocarbon group include a cycloalkyl group and a cycloalkyl group. Alkenyl groups, phenyl groups, and the like.Examples of the polycyclic hydrocarbon group include a naphthyl group, a tetrahydronaphthyl group, a condensed polycyclic hydrocarbon group such as an indanyl group or an adamantyl group, a noradamantyl group, and a norbornanyl group. Examples include a crosslinked polycyclic hydrocarbon group such as a norbornanonyl group, and the monocyclic heterocyclic group includes a pyrrolyl group, a furanyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group,
Isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrrolinyl group, pyrrolidinyl group, dihydrofuranyl group, tetrahydrofuranyl group, dihydrothienyl group, tetrahydrothienyl group, pyrazolinyl group, hydantoinyl group, oxazolinyl group, isoxazolinyl group, Isoxazolidinyl group, thiazolinyl group, thiazolidinyl group, dioxolanyl group, dithialanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, dihydrooxopyridazinyl group, Tetrahydrooxopyridazinyl group, dihydrooxopyrimidinyl group, tetrahydrooxopyrimidinyl group, piperazinyl group, dihydropyranyl group, tetrahydropyranyl group, dioxo And the like. Examples of the polycyclic heterocyclic group include a thienothienyl group, a dihydrocyclopentathienyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, and a benzoxayl group. Zolyl group, benzisoxazolyl group, benzothiazolyl group, benzimidazolyl group, tetrahydrobenzothienyl group, dihydrobenzofuranyl group, tetrahydrobenzisoxazolyl group, benzodioxolyl group, quinolinyl group, isoquinolinyl group, benzo Examples include a condensed polycyclic heterocyclic group such as a dioxanyl group and a quinoxalinyl group, and a crosslinked polycyclic heterocyclic group such as a quinuclidinyl group.

The substituent of the optionally substituted chain hydrocarbon group contained in R ¹¹ is a halogen atom, an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyl group. An oxy group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an aryl group, an aryloxy group, an arylthio group, an amino group, an amino group substituted with an alkyl group, and the like; The number of substituents attached to these substituents may be one or two or more, and when two or more, the substituents may be the same or different.

Further, optionally substituted monocyclic hydrocarbon group contained in R ^11, which may be substituted polycyclic hydrocarbon group, be being and monocyclic heterocyclic group may be substituted substituted Preferred substituents of the polycyclic heterocyclic group include a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, and an alkoxycarbonyl group. Group, an alkylcarbonyl group, an alkylcarbonyloxy group, an aryl group, an aryloxy group, an arylthio group, an amino group, an amino group substituted with an alkyl group, a cyano group, a nitro group, a hydroxyl group, and the like. The number of substituents attached to those substituents may be one, two or more, and two or more. In these cases, those substituents may be the same or different.

In the general formula (I), the alkyl group and the alkyl moiety contained in R ¹¹ include those having 1 to 18 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, Examples include a heptyl group, an octyl group, a decyl group, a nonadecyl group, and the like, including those having a linear or branched fatty chain structural isomer. R ¹¹
Include alkenyl groups having 2 to 18 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl, nonadecenyl, and the like. Includes structural isomers of branched fatty chains. Examples of the alkynyl group included in R ¹¹ include those having 2 to 18 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a decynyl group, and a nonadecynyl group.
They also include those having structural isomers of linear or branched fatty chains. As the cycloalkyl group and the cycloalkyl moiety contained in R ¹¹ , those having 3 to 8 carbon atoms, for example,
Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Examples of the cycloalkenyl group and cycloalkenyl moiety contained in R ¹¹ include those having 5 to 8 carbon atoms, such as a cyclopentenyl group, a cyclohexenyl group, and a cyclooctenyl group. Further, as a halogen atom contained in R ¹¹ , a fluorine atom, a chlorine atom, a bromine atom,
And iodine atoms. The aryl group and the aryl moiety contained in R ¹¹ include a phenyl group, a thienyl group,
Examples include a furanyl group, a pyridyl group, a naphthyl group, a benzothienyl group, a benzofuranyl group, and a quinolinyl group.

The enopyranose derivative represented by the general formula (I) has a stereoisomer based on the fact that the carbon atoms at the 1-, 2- and 5-positions of the pyranose ring are asymmetric carbons. The present invention also covers them. Examples of the salt of the enopyranose derivative represented by the general formula (I) include acid addition salts with mineral acids such as hydrochloric acid and sulfuric acid.

It is desirable that the enopyranose derivative represented by the general formula (I) is as follows. (1) An enopyranose derivative represented by the following general formula (I-1)
Or a stereoisomer represented by (I-2).

[0021]

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(Wherein R ^{1 to} R ⁶ , X and Y are as described above.) (2) In the general formula (I-1) or (I-2), R ¹
Is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group or an alkynyl group, R ² is a hydrogen atom or an alkyl group, R ³ and R ⁶ are each a hydrogen atom,
R ⁴ and R ⁵ together form a single bond;
And Y are the enopyranose derivatives as described above. Those of the general formula (I-1) are more desirable.

The enopyranose derivatives represented by the general formula (I) include novel compounds. The present invention also relates to those compounds listed below. In the general formula (I-1) or (I-2), R ¹ is a hydrogen atom,
An optionally substituted alkyl group, an alkenyl group, an alkynyl group, -OSO ₂ R ⁷ group, a halogen atom, -OCOR ⁷
R ² is a hydrogen atom or an alkyl group, R ³ is a hydrogen atom or a halogen atom, R ⁴ is a group represented by the group: —NHCOR ⁸ group, an alkoxy group, an optionally substituted phenyl group or a sugar derivative residue. R ⁵ together form a single bond, R ⁶ is a hydrogen atom or an optionally substituted alkyl group, R ⁷ is an alkyl group or an optionally substituted phenyl group, and R ⁸ is an alkyl group X is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cyclo group which may be substituted. Alkyl group, optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted furanyl group, optionally substituted thienyl group, formyl group, -CO
R ¹¹ groups, —C (W ¹ ) W ² R ¹¹ groups or —SO ₂ R
A ¹¹ group, R ¹¹ is an optionally substituted chain hydrocarbon group may be substituted monocyclic hydrocarbon group may be substituted polycyclic hydrocarbon group, an optionally substituted monocyclic A heterocyclic group or a polycyclic heterocyclic group which may be substituted, W ¹ is an oxygen atom or a sulfur atom, W ² is an oxygen atom, a sulfur atom or a —NH— group, and Y is a hydrogen atom A compound which is an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group. However, the following cases are excluded. In (I-1), R ¹ , R ² , R ³ , R ⁶ and X
Is a hydrogen atom, and Y is a hydrogen atom or an alkyl group which may be substituted, in (I-1), R ¹ , R ² , R ³ , R ⁶ and Y
Is a hydrogen atom, and when X is acetyl, 3,5-dinitrobenzoyl or p-toluenesulfonyl, in (I-1), R ¹ , R ² , R ³ and Y are hydrogen atoms and R ⁶ Is an alkyl group which may be substituted, and when X is a hydrogen atom or acetyl, in (I-2), R ¹ , R ² , R ³ , R ⁶ and X
Is a hydrogen atom, and Y is methyl; in (I-2), R ¹ , R ² , R ³ , R ⁶ and Y
Is a hydrogen atom, X is a hydrogen atom, methyl, benzyl,
Formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl In certain cases, and in (I-2), R ¹ is p-toluenesulfonyloxy, R ² , R ³ , R ⁶ and Y are hydrogen atoms, and X is a hydrogen atom, acetyl or p-toluenesulfonyl. If there is.

The following compounds are desirable as the compound of the present invention. (1) In the general formula (I-1), R ¹ is a hydrogen atom, an optionally substituted alkyl group, an alkenyl group or an alkynyl group, R ² is a hydrogen atom or an alkyl group,
A compound wherein ³ and R ⁶ are each a hydrogen atom, and R ⁴ and R ⁵ together form a single bond. (2) In the general formula (I-1), X may be an alkyl group which may be substituted or -COR ¹¹ (R ¹¹ is as described above), more preferably furfuryl or -COR ¹¹ (R
¹¹ is an optionally substituted furanyl), and R ¹ ,
A compound wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in (1) above. (3) The compound in the formula (I-1), wherein X is furancarbonyl or furfuryl. (4) The compound represented by formula (I-1), wherein Y is an alkynyl group which may be substituted.

Further, the following compounds or salts thereof are most desirable. 1,6-anhydro-3,4-dideoxy-2-O
-(2-furancarbonyl) -β-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-
Dideoxy-2-O- (2-furancarbonyl) -3-
Methyl-β-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-C
-Ethynyl-2-O- (2-furancarbonyl) -β-
D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O- (2-furfuryl) -3-methyl-β-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O- (2-furfuryl) -β-D-threo-hex-3-enopyranose or 1,6-anhydro-
3,4-dideoxy-2-C-ethynyl-2-O- (2
-Furfuryl)-[beta] -D-threo-hex-3-enopyranose.

The enopyranose derivative represented by the general formula (I) or a salt thereof can be produced by various methods. For example, 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose can be reduced to 1,6-anhydro-3,4
After once producing -dideoxy-β-D-threo-hex-3-enopyranose, this is acylated, carbonated, carbamide esterified, etherified or sulfonylated by a conventional method to produce a desired compound. Also, 1,6-anhydro-3,4-dideoxy-β-D
-Glycero-hex-3-enopyranose-2-ulose is alkylated, alkenylated or alkynylated at the 2-position in a conventional manner to produce the desired compound. The 2-position reactant is further acylated, carbonated, carbamide esterified, etherified or sulfonylated as described above to produce the desired compound. On the other hand, 1,6-anhydro-3,4-
Dideoxy-β-D-erythro-hex-3-enopyranose can be obtained by the above-mentioned reduction reaction, but can also be produced by isomerization of the threo form. Further, this compound can be acylated, carbonated, carbamide esterified, etherified or sulfonylated by a conventional method to produce a desired compound.

In addition, instead of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose, the following compound represented by the general formula (II) is used. be able to. The general formula (I
I)

[0028]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as described above) The compound represented by the general formula (II) is reduced or alkylated by a conventional method. , Alkenylation or alkynylation and acylation, carbonation, carbamide esterification, etherification or sulfonylation in the usual manner to produce the desired compound. Further, the compound represented by the general formula (II) is reduced and then isomerized,
The desired compound can be produced by acylation, carbonation, carbamide esterification, etherification or sulfonylation by a conventional method.

The compound represented by the general formula (II) has an enantiomer (L-form), and the compound can be used to carry out the same reaction as described above. In carrying out these reactions, by carrying out the reaction in an inert atmosphere such as nitrogen gas, helium gas, argon gas or the like, side reactions and reduction in yield can be prevented. The general production method using these reactions is described below.

A. Dry ether solution containing reduced 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or water containing it or an alcohol solution such as methanol, ethanol or isopropanol To lithium aluminum hydride or sodium borohydride of 0.3 equivalent or more, preferably 0.4 to 0.5 equivalent, respectively. The reaction is carried out by stirring the reaction mixture at room temperature or lower, preferably at -10 to 0 ° C for 0.5 to 2 hours. After adding a small amount of water to the reaction product, post-treatment is carried out by a conventional method to carry out purification and separation.

B. Acylation A suitable acyl halide is added to a dry pyridine solution containing a reduced form of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or a 2-position reactant thereof. 1 equivalent or more, desirably 1.5 to
Add 2 equivalents slowly. The reaction is carried out by stirring the reaction mixture at room temperature or lower, preferably at -10 to 0 ° C for 0.5 to 2 hours. After adding a small amount of water to the reaction product, it is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

When direct acylation is carried out using a carboxylic acid instead of an acyl halide, 1,6-anhydro-
1.5 to 2 equivalents of dicyclohexylcarbodiimide, diethylcarbodiimide and the like, and 1.5 to 2 equivalents of a suitable carboxylic acid, based on a dry methylene chloride solution containing 3,4-dideoxy-β-D-threo-hex-3-enopyranose. Then, 0.1 to 0.2 equivalents of N, N-dimethylaminopyridine, diisopropylethylamine and the like as a catalyst are added, and the reaction is carried out with stirring at 0 to 30 ° C, preferably 10 to 20 ° C for 6 to 12 hours. Purification and separation are carried out by post-treatment in a conventional manner.

C. In a dry pyridine solution containing a reduced form of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or a 2-position reactant thereof,
2 equivalents or more of a suitable chlorocarbonate, preferably 2 equivalents
The reaction is carried out by gradually adding ３3 equivalents and stirring the reaction mixture at 0-30 ° C., preferably 10-20 ° C. for 6-12 hours. After adding a small amount of water to the reaction product, post-treatment is carried out by a conventional method to carry out purification and separation.

D. Carbamate esterification Suitable for a dry toluene solution containing a reduced form of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or its 2-position reactant 1.3 equivalents or more, desirably 1.5 to 2 equivalents of an isocyanate or isothiocyanate is gradually added thereto, and the mixture is stirred for 10 to 15 minutes, and 0.1 to 0.2 equivalents of diisopropylethylamine, triethylamine or the like or hydrogenated. 0.8 to 1.2 equivalents such as sodium and potassium hydride are added, respectively, and the mixture is further stirred and reacted. The reaction in the case where triethylamine or the like is added requires reflux under heating.

When phenyl isocyanate is used, diisopropylethylamine, triethylamine and the like are desirable. In other cases, potassium hydride, sodium hydride and the like are desirable. After completion of the reaction, the reaction product is post-treated by a conventional method to perform purification and separation.

E. Etherification The reduced form of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or its 2-position reactant is converted to a sodium hydride or potassium hydride or the like. The base is slowly added to a suspension of 1.0 to 1.5 equivalents, preferably 1.3 equivalents, of dry tetrahydrofuran. The reaction mixture is cooled to 0-20 ° C, preferably 0-10 ° C.
After stirring at 10 ° C. for 10 to 15 minutes, an appropriate organic halide is added in an amount of 1 equivalent or more, preferably 1.3 to 1.5 equivalents.
The reaction is carried out by stirring at 〜30 ° C., preferably 20-30 ° C. for 6-12 hours. The above-mentioned organic halide is selected according to a desired target, and for example, methyl iodide, butyl iodide, benzyl bromide and the like can be used. After adding a small amount of water to the reaction product, it is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

F. Sulfonylation A dried pyridine solution containing a reduced form of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or a 2-position reactant thereof is added with 1
Equivalent or more, desirably 1.5 to 2 equivalents of a suitable sulfonyl halide is gradually added, and the reaction mixture is heated at 10 to 30 ° C.
Preferably, the reaction is carried out by stirring at 20 to 30 ° C. for 6 to 12 hours. The above-mentioned sulfonyl halide is selected according to the desired object, and for example, tosyl chloride, mesyl chloride and the like can be used. After adding a small amount of water to the reaction product, extraction is performed with a solvent such as toluene, and the solvent is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

G. Alkylation, alkenylation or alkynylation Alkyl, alkenyl or alkynyllithium suitable for dry tetrahydrofuran solution containing 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose Alternatively, 1.2 to 1.5 equivalents of each alkylating, alkenylating or alkynylating organometallic reagent such as alkyl, alkenyl or alkynyl magnesium bromide is added slowly. The reaction mixture was
The reaction is carried out by stirring at 8 to 0 ° C, preferably -10 to 0 ° C for 0.5 to 1 hour. A small amount of water is added to the reaction mixture, and the mixture is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

H. Isomerization To a solution of the reduced form of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or the tosyl ester of the 2-position reactant in dry dimethylformamide solution, benzoic acid was added. The reaction is carried out by adding 1 to 2 equivalents, preferably 2 equivalents of a metal salt of a carboxylic acid such as sodium acid and stirring at 100 to 150 ° C., preferably at reflux temperature for 30 minutes. The reaction mixture was post-treated by a conventional method, and after removing the solvent, the residue was dissolved in dry methanol, and 1 to 2 equivalents, desirably 1.5 equivalents of a base was added, and 0 to 30
The reaction is carried out by stirring at 30 ° C., preferably at 20 to 30 ° C. for 30 minutes. As the aforementioned base, sodium hydroxide, potassium hydroxide, sodium methoxide and the like can be used. After completion of the reaction, purification and separation are carried out by post-treatment according to a conventional method.

The compound represented by the general formula (II) can be produced by various methods. For example, 1,
The desired compound is produced by halogenating the 3-position of 6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose, and the 3-position reactant is further subjected to a coupling reaction. Can be alkylated, alkenylated, alkynylated, or arylated to produce a desired compound. Also, 1,6-anhydro-3,
4-Dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or a 3-, 4- or 5-substituted derivative thereof is treated under acidic conditions, and the 1-position is etherified simultaneously with the ring-opening of the acetal. Or acylation at the 1- and 6-positions to produce the desired compound. Further, the desired compound can be produced by etherifying, acylating, or silylating the 6-position of the compound obtained by etherifying the 1-position. The resulting compound can be deacylated at position 1 or 1 and 6 by hydrolysis. On the other hand, a natural ketone such as glucose, galactose or mannose can be used as a raw material to produce a 2-ketone derivative by oxidation to produce a desired enone derivative having an oxygen or nitrogen functional group at the 3-position.

In carrying out these reactions, the reactions are usually carried out in an inert atmosphere such as nitrogen gas, helium gas, argon gas or the like, whereby side reactions and reduction in yield can be prevented. Hereinafter, a general production method using these reactions will be described.

A. Halogenation reaction (A-1) Bromination Halogenation of dry carbon tetrachloride containing 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose, chloroform and the like. 0.9 or more, desirably 1.5 to 2 equivalents of bromine is slowly added to the carbon solution at 0 ° C or less, preferably at -10 to -15 ° C. The reaction mixture is kept at 0 ° C. or lower, preferably -10 to -1.
The reaction is carried out by stirring at 5 ° C. for 10 to 30 minutes. A base such as pyridine, triethylamine, diisopropylethylamine or the like is added in an amount of 5 equivalents or more, preferably 8 to 10 equivalents.
The reaction is carried out by stirring for hours. After adding water to the reaction solution, post-treatment is carried out by a conventional method to carry out purification and separation.

(A-2) Iodination In a dry pyridine-carbon tetrachloride solution containing 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose, 5 A dry pyridine-carbon tetrachloride solution of iodine in an amount of at least an equivalent, preferably 8 to 10 equivalents, is gradually added at 5 ° C or less, preferably at 0 to 5 ° C.
The reaction is carried out by stirring the reaction mixture at room temperature, preferably at 15 to 25 ° C. for 2 hours. After adding ethyl acetate, post-treatment is carried out by a conventional method to carry out purification and separation. See Car for this method.
lR. Synthesized according to the method of Johnson et al. [T
etrahedron Lett. 33.917-91
8. (1992)]. For the synthesis of α-iodine derivatives directly from enones, see John M. et al. McIntosh
[Can. J. Chem. 49,3045-30
47, (1971)]. H. Kim et al. [C
hem. Express 5, 221, (1990)]
There is.

B. Coupling reaction 1,6-anhydro-3,4-dideoxy-3-iodo-β-D-glycero-hex-3-enopyranose-2
-In dry N-methylpyrrolidinone solution containing urose,
0.01-0.3 equivalents, preferably 0.05-0.15 equivalents of copper (I) iodide, 0.01-0.3 equivalents, preferably 0.1-0.3 equivalents.
0.5 to 0.15 equivalents of triphenylarsenic, 0.01 to
The reaction is carried out using 0.1 equivalent, desirably 0.03 to 0.07 equivalent of a palladium-based catalyst such as bis (benzonitrile) palladium (II) chloride. An organic tin compound or an organic zinc compound is added to the reaction mixture, and the reaction is performed at 0 to 100 ° C, preferably 25 to 80 ° C, for 1 to 10 hours, preferably 2 to 6 hours. After adding ethyl acetate, post-treatment is carried out by a conventional method to carry out purification and separation. This method is described in C.I. R. Jo
hnson et al. [Tetrahedron Let
t. 33, 919-922, (1992)].

When R ¹ in the general formula (II) is an optionally substituted alkyl group, the following method can be used. That is, 1,6-anhydro-3-bromo-
3,4-dideoxy-β-D-glycero-hex-3-
Enopyranose-2-ulose was reacted with at least one equivalent of ethylene glycol and a catalytic amount of paratoluenesulfonic acid at the reflux temperature of a solvent such as benzene or toluene to protect the carbonyl group at the 2-position of the pyranose ring.
6-anhydro-3-bromo-3,4-dideoxy-β
-D-Glycero-hex-3-enopyranose-2-ulose ethylene acetal is obtained, which is then dissolved in a solvent such as tetrahydrofuran with at least one equivalent of n-butyllithium and at least one equivalent of alkyl iodide at -60. ~
The reaction is performed at a reaction temperature of -80 ° C. After the reaction, the protecting group at the 2-position of the pyranose ring is eliminated together with a catalytic amount of p-toluenesulfonic acid at the reflux temperature of tetrahydrofuran and water. Various ketones or aldehydes can be used in place of the aforementioned alkyl iodide. In that case, a compound having an alkyl group substituted with a hydroxyl group as R ¹ is obtained. Further, when an alcohol such as methanol is used as a solvent in the reaction for removing the protecting group, the hydroxy portion of the alkyl group substituted with the hydroxyl group can be converted to an alkoxy group such as methoxy. Also,
The hydroxy part of an alkyl group substituted with a hydroxyl group can be aminated by a known method.

C. Ring opening reaction of acetal 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose or its 1, 3-, 4- or 5-substituted derivative A suitable acid anhydride or a corresponding acid anhydride in a dry chloroform solution is mixed with sulfuric acid or a Lewis acid such as boron trifluoride / etherate at -20 ° C to 15 ° C, preferably at -10 ° C to 0 ° C. 0.05 to 0.5 equivalents, desirably 0.08 to 0.15 equivalents are gradually added. After the reaction mixture is stirred for 10 minutes to 2 hours, preferably 15 to 30 minutes, the reaction solution is added to ice-saturated aqueous sodium hydrogen carbonate, and then purified and separated by a conventional method. [Carbohydr, Res. 7
1, 169-191 (1979)]

On the other hand, when synthesizing a 1-alkoxy derivative, 1-5%, preferably 3-4%, of concentrated sulfuric acid is added to a corresponding alcohol solution such as methanol, ethanol, propanol, etc. 15-25
The mixture is stirred at a temperature of 5 to 48 hours, preferably 12 to 36 hours.
After the reaction solution is neutralized with a base such as sodium hydrogen carbonate, it is purified and separated by a conventional treatment. The alcohol at the 6-position generated at this time can be converted to the corresponding derivative by etherification, acylation, or the like by a conventional method.

D. Hydrolysis 1,6-di-O-acyl-3,4-dideoxy-α-D
-Glycero-hex-3-enopyranose-2-ulose or a water solution containing a 1-, 3-, 4- or 5-substituted derivative thereof or an alcohol solution of methanol, ethanol, isopropanol, etc., in lithium hydroxide or sodium hydroxide And 0.05 to 0.3 equivalents, preferably 0.1 to 0.15 equivalents, of a base such as potassium hydroxide.
Preferably at 15-25 ° C for 10-45 minutes, preferably 20
Stir for ~ 30 minutes. After adding ethyl acetate to the reaction product, the precipitate is removed by filtration and concentrated under reduced pressure to obtain a product, which is purified and separated by a conventional method.

E. Oxidation reaction To a dry methylene chloride solution containing 3,4-dideoxy-hex-3-enopyranose or a derivative thereof, 1 to 10 equivalents, preferably 2 to 5 equivalents of pyridinium chlorochromate is added, and 0 to 40 ° C, preferably 10 to 10 equivalents. 1-2 at ~ 20 ° C
The reaction is carried out with stirring for 0 hour, preferably for 2 to 12 hours. Diethyl ether was added, the mixture was filtered through silica gel, and the filtrate was concentrated to obtain a crude product, which was purified and separated by a conventional method.
The compound represented by the general formula (II) includes compounds not described in the literature. For example, the general formula (II ′)

[0051]

Embedded image

(Wherein R ¹ ′ represents an optionally substituted alkyl group, alkenyl group, alkynyl group, —OSO ₂ R
⁷ groups, a halogen atom, a phenyl group which may be substituted or a sugar derivative residue, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described above. However, this excludes the case where R ¹ ′ is a bromine atom, R ⁴ and R ⁵ form a single bond, and R ⁶ is a hydrogen atom. ) Or a salt thereof is a novel compound.

Further, the compound represented by the general formula (II) also has an inhibitory effect on immune function. Next, the enone derivatives represented by the general formula (II) are shown in Tables 1 and 2.
An example is shown below.

[0054]

[Table 1]

[0055]

[Table 2]

Intermediate Synthesis Example 1 1,6-Anhydro-
3,4-dideoxy-3-iodo-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 5) Under an inert atmosphere of nitrogen gas, 1,6-anhydro-3,
4-Dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose (U.S. Pat.
To a solution of 5 g of dry pyridine-carbon tetrachloride (1: 1) 150 ml of a solution of 40 g of iodine in 150 ml of dry pyridine-carbon tetrachloride (1: 1) was slowly added at 0 ° C. After stirring at room temperature for 2 hours, disappearance of the starting materials was confirmed by thin layer chromatography, and 200 ml of ethyl acetate was added. 2 times with 200 ml of saturated saline,
Washed once with 200 ml of 0% sodium thiosulfate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained syrupy crude product is subjected to silica gel column chromatography (ethyl acetate: hexane =
1: 3) to give 6.1 g of the desired product (Intermediate No. 5) as pale yellow crystals. Its NMR analysis values and physical properties are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.81
(1H, d, J = 6.8 Hz); 3.87 (1H, d
d, J = 6.8, 5.0 Hz); 4.93 (1H, t,
J = 5.0 Hz); 5.57 (1H, s); 7.96
(1H, d, J = 5.0 Hz) m. p. 66-67 ° C

Intermediate Synthesis Example 2 1,6-Anhydro-
3,4-dideoxy-3-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 2) Under an inert atmosphere of nitrogen gas, 1,6-anhydro-3,
5 g of 4-dideoxy-3-iodo-β-D-glycero-hex-3-enopyranose-2-ulose, 0.4 g of cuprous iodide, 0.6 g of triphenylarsenic and bis (benzonitrile) palladium chloride ( II) To 20 ml of a dry N-methylpyrrolidinone solution containing 0.4 g of the mixture was added 5.3 g of tetramethyltin, and the mixture was stirred at 80 ° C for 4 hours. 200 ml of ethyl acetate was added, and the mixture was washed three times with 100 ml of a 10% aqueous potassium fluoride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting syrupy product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3), and then distilled under reduced pressure to obtain the target product (intermediate No. 2) as a colorless transparent liquid. 0.61 g was obtained. NM of this thing
The analytical values of R are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.79
(3H, s); 3.68 (1H, d, J = 6.8H)
z); 3.83 (1H, dd, J = 6.8, 4.8H
z); 4.95 (1H, t, J = 4.8 Hz); 5.3
6 (1H, s); 6.96 (1H, dq, J = 4.8,
1.6 Hz) b. p. 150-170 ° C (40 mmHg) The following compounds were synthesized according to the case of Intermediate Synthesis Example 2, and their physical properties are described.

Intermediate No. 42 ¹ H NMR (CDCl ₃ , 400 MHz): 2.36
(3H, s); 3.85 (1H, d, J = 6.6H)
z); 3.95 (1H, dd, J = 6.6, 4.8H)
z); 5, 15 (1H, t, J = 4.8 Hz); 5.5
0 (1H, s); 7.19 (2H, br, d, J = 8.
7.23 (1H, d, J = 4.8 Hz);
7.32 (2H, br, d, J = 8.1 Hz) m. p. 117-119 ° C

Intermediate No. 9 ¹ H NMR (CDCl ₃ , 400 MHz): 1.82
(1H, dt, J = 11.5, 4.8 Hz); 1.90
(1H, m); 1.98 (1H, dt, J = 11.5,
3.32); 2.22 (1H, m); 2.64 (1
H, dddd, J = 20.0, 3.5, 3.5, 3.5
Hz); 3.15 (1H, m); 3.62 (1H, d,
J = 6.9 Hz); 3.68 (1H, d, J = 7.3H)
z); 3.79 (1H, dd, J = 7.3, 4.7H)
z); 3.87 (1H, dd, J = 6.9, 4.3H)
z); 4.40 (1H, d, J = 4.7 Hz); 5.0
1 (1H, t, J = 4.7 Hz); 5.17 (1H,
s); 5.35 (1H, s); 6.80 (1H, dd,
J = 4.7, 1.2 Hz); 6.93 (1H, q, J =
3.5Hz)

Intermediate Synthesis Example 3 Synthesis of methyl 3,4-dideoxy-3-methyl-α-D-glycero-hex-3-enopyranose-2-ulose (intermediate No. 20) 1,6-anhydro- 3,4-dideoxy-3-methyl-β-D-glycero-hex-3-enopyranose-2
-0.1 ml of concentrated sulfuric acid was added to 30 ml of a dry methanol solution of 500 mg of urose (intermediate No. 2), and
Stir for 8 hours. 30 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 15 minutes and concentrated under reduced pressure. To this, add 200 ml of ethyl acetate and add 200 ml of saturated saline.
And washed three times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 350 mg of the desired compound (intermediate No. 20) as a colorless liquid. Its NMR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.86
(3H, m); 1.95 (1H, t, J = 6.0H)
z); 3.54 (3H, s); 3.76 (1H, dd)
d, J = 11.2, 6.8, 6.0 Hz); 3.84
(1H, ddd, J = 11.2, 6.0, 3.6H
z); 4.63 (1H, m,); 4.80 (1H,
s); 6.68 (1H, m)

Intermediate Synthesis Example 4 1,6-Di-O-propionyl-3,4-dideoxy-α-D-glycero-hex-3-enopyranose-2-ulose (Intermediate No.
Synthesis of 19) 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose 1
00 mg in 3 ml of propionic anhydride,
Until cooled. 0.06 ml of concentrated sulfuric acid was added thereto, and 30
After stirring for 10 minutes, the reaction mixture was added to 100 ml of ice-saturated aqueous sodium hydrogen carbonate. After stirring for 30 minutes, the mixture was extracted with 100 ml of ethyl acetate and washed three times with 100 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained syrupy crude product is subjected to silica gel chromatography (ethyl acetate: hexane =
1: 2) to give the desired product (intermediate No. 1)
9) was obtained as a colorless transparent liquid (100 mg). Its NMR analysis values are as follows.

Intermediate No. 19 ¹ H NMR (CDCl ₃ , 400 MHz): 1.14
(3H, t, J = 5.2 Hz); 1.16 (3H, t,
J = 5.2 Hz); 2.38 (4H, m); 4.22
(1H, dd, J = 11.4, 4.6 Hz); 4.41
(1H, dd, J = 11.4, 4.7 Hz); 4.81
(1H, m,); 6.20 (1H, s); 6.28 (1
H, dd, J = 10.6, 2.4 Hz); 7.05 (1
(H, dd, J = 10.6, 1.9 Hz) The following compounds were synthesized in the same manner as in Synthesis Example 4 above, and their physical properties are described.

Intermediate No. 16 ¹ H NMR (CDCl ₃ , 400 MHz): 2.10
(3H, s); 2.13 (3H, s); 4.20 (1
H, dd, J = 11.4, 5.0 Hz); 4.38 (1
H, dd, J = 11.4, 5.0 Hz); 4.88 (1
H, td, J = 5.0, 1.9 Hz); 6.34 (1
H, s); 7.43 (1H, d, J = 1.9 Hz)

Intermediate Synthesis Example 5 6-O-acetyl-3-
Bromo-3,4-dideoxy-D-glycero-hexo-
3-enopyranose-2-ulose (intermediate No. 1
8) Synthesis of Carbohydrate Research 198
1 year, 93, 284-287, 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose. 1,6-di-O-acetyl-3- synthesized from (Intermediate No. 4) according to the above-mentioned Synthesis Example 4.
Dissolve 200 mg of bromo-3,4-dideoxy-α-D-glycero-hex-3-enopyranose-2-ulose in 6 ml of tetrahydrofuran-water (5: 1), add 70 mg of lithium hydroxide-hydrate and add room temperature. For 30 minutes. 100 ml of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 100 ml of saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by preparative thin-layer chromatography (Merck, NO-5744, ethyl acetate: hexane =
1: 1) to give the desired product (intermediate No. 1).
8) was obtained as a pale yellow liquid in an amount of 40 mg. N of this thing
The analysis values of MR are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.12
(0.9H, s); 2.13 (0.1H, s); 4.2
4 (0.1 H, dd, J = 11.2, 5.0 Hz);
4.26 (0.9H, dd, J = 11.5, 5.0H
z); 4.35 (0.9H, dd, J = 11.5, 5.
0 Hz); 4.47 (0.1H, dd, J = 11.2,
4.78 (0.1H, dddd, J =
6.5, 5.0, 1.9, 1.0 Hz); 5.00
(0.9H, td, J = 5.0, 2.2Hz); 5.3
1 (0.1H, br, s); 5.46 (0.9H, b
r, s); 7.38 (0.9H, d, J = 2.2H
z); 7.44 (0.1 H, d, J = 1.9 Hz) The following compounds were synthesized according to Synthesis Example 5, and their physical properties are described.

Intermediate No. 17 ¹ H NMR (CDCl ₃ , 400 MHz): 2.09
(2.25H, s); 2.10 (0.75H, s);
4.26 (0.25H, dd, J = 11.5, 5.0H
z); 4.27 (0.75H, dd, J = 11.5,
4.34); 4.34 (0.75H, dd, J = 1)
1.5, 5.3 Hz); 4.42 (0.25H, dd,
J = 11.5, 6.2 Hz); 4.79 (0.25H,
m); 4.93 (0.75H, m); 5.19 (0.2
5H, br, d, J = 5.7 Hz); 5.26 (0.7
5H, br, d, J = 3.3 Hz); 6.19 (0.7
5H, dd, J = 10.4, 2.5 Hz); 6.27
(0.25H, dd, J = 10.0, 2.8Hz);
6.99 (0.75H, dd, J = 10.4, 1.7H
z); 6.99 (0.25H, dd, J = 10.0,
1.9Hz)

Intermediate Synthesis Example 6 1,6-Anhydro-3
-Op-toluenesulfonyl-4-deoxy-β-D
Synthesis of -glycero-hex-3-enopyranose-2-ulose (intermediate No. 3) 1,6-anhydro-3-Op-toluenesulfonyl-4-deoxy-β-D-erythro-hexo-3 -20 mg of a dry methylene chloride solution of 50 mg of enopyranose
Was added with 360 mg of pyridinium chlorochromate,
Stirred at room temperature for 48 hours. The disappearance of the starting material was confirmed by thin layer chromatography, and 60 ml of diethyl ether was added. After stirring at room temperature for a further 15 minutes, the reaction mixture was filtered over silica gel and washed with 200 ml of diethyl ether. The washing solution was concentrated under reduced pressure together with the filtrate. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 34 mg of the desired product (Intermediate No. 3) as a colorless transparent liquid. Its NMR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.45
(3H, s); 3.83 (1H, d, J = 7.2H)
z); 3.92 (1H, dd, J = 7.2, 4.8H)
z); 5.14 (1H, t, J = 4.8 Hz); 5.3
6 (1H, s); 7.17 (1H, d, J = 4.8H)
z); 7.35 (2H, br, d, J = 8.0 Hz);
7.82 (2H, dt, J = 8.8, 2.0 Hz) m. p. 81-86 ° C

Intermediate Synthesis Example 7 1,6-Anhydro-
3,4-dideoxy-4-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 43) Diisopropylamine in an inert atmosphere of nitrogen gas.
From 45 ml (mmol) and 1.75 ml of butyllithium, 1,6-anhydro-3,1,6-anhydro-3, was added to a lithium amide solution prepared in a usual manner in 25 ml of anhydrous tetrahydrofuran.
4-dideoxy-4-C-methyl-β-D-erythro-
Hexopyranose-2-ulose (Carbohydr)
ate Res. 71, (1979) 169) 3
A solution of 00 mg in 1 ml of tetrahydrofuran was added at -78 ° C. After stirring for 1 hour, 500 mg (mmol) of phenylselenyl chloride and 3 ml of a tetrahydrofuran solution of 0.75 ml of hexamethyltriamide phosphate were added, and the mixture was stirred at -78 ° C for 30 minutes. A saturated aqueous ammonium chloride solution was added, the solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. After washing twice with a saturated saline solution, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a syrupy crude product. This was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain 106 mg of a selenium derivative.

The selenium derivative obtained by the above reaction was dissolved in 20 ml of dry methylene chloride under an inert atmosphere of nitrogen gas, and 60 mg of m-chloroperbenzoic acid was added at -78 ° C. After stirring for 20 minutes, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with methylene chloride. The organic layers were combined, washed twice with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel thin layer chromatography (methylene chloride) to give the desired 1,6-anhydro-
3,4-dideoxy-4-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. 43) 1.7 mg were obtained as a colorless transparent liquid. The NMR analysis value of this product is as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 2.08
(3H, d, J = 1.2 Hz); 3.71 (1H, d,
J = 6.8 Hz); 3.91 (1H, dd, J = 6.
4.80 (1H, d, J = 4.8H)
z); 5.32 (1H, d, J = 1.2 Hz); 5.8
7 (1H, m)

Intermediate Synthesis Example 8 1,6-Anhydro-
3,4-dideoxy-3-ethyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 46) [1] 1,6-Anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose 22 g was dissolved in dry benzene 500 ml, and ethylene glycol was dissolved. 66 g and 3 g of p-toluenesulfonic acid monohydrate were added, and the mixture was heated to reflux while removing generated water. After 19 hours, disappearance of the starting materials was confirmed by TLC, and the reaction mixture was cooled to room temperature. 500 ml of ethyl acetate was added thereto, and the mixture was washed three times with 200 ml of saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude crystals are subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purified in 1), 1,6-anhydro-3-bromo-3,
4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose ethylene acetal 20
g were obtained as white crystals. Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.71
(1H, dd, J = 6.8, 4.4 Hz); 3.79
(1H, d, J = 6.8 Hz); 4.04 (1H,
m); 4.17 (1H, m); 4.28 (2H, m);
4.75 (1H, t, J = 4.4 Hz); 5.28 (1
H, s); 6.60 (1H, d, J = 4.4 Hz) m. p. 111-112 ° C

[2] The 1,6-anhydro-3-bromo-3,4-dideoxy-β-D- obtained in the above [1]
3 g of glycero-hex-3-enopyranose-2-ulose ethylene acetal was dissolved in 200 ml of dry tetrahydrofuran, and 1.2 equivalents of n-butyllithium was added thereto with stirring at -78 ° C under a nitrogen atmosphere. After stirring for 20 minutes, 1.9 ml of ethyl iodide was added to the obtained mixture.
And a solution of 5.2 ml of hexamethylphosphamide in 10 ml of anhydrous tetrahydrofuran. After stirring for 30 minutes, the temperature was gradually raised to room temperature. After confirming the completion of the reaction by TLC, a small amount of water was added and the solvent was distilled off under reduced pressure.
300 ml of ethyl acetate was added to the residue, and the mixture was washed three times with 100 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 1,6-anhydro-3,4-dideoxy. -3-Ethyl-β-D-glycero-hex-3-enopyranose-2
1.48 g of urose ethylene acetal was obtained as white crystals. Its NMR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.03
(3H, t, J = 7.2 Hz); 2.03 (1H,
m); 2.11 (1H, dqd, J = 16.6,7.
2.2.0 Hz); 3.70 (2H, m); 4.00-
4.10 (3H, m); 4.16 (1H, m); 4.7
4 (1H, m); 5.19 (1H, s); 5.94 (1
H, dt, J = 4.4, 2.0 Hz)

[3] The 1,6-anhydro-3,4-dideoxy-3-ethyl-β-D- obtained in the above [2]
1.47 g of glycero-hex-3-enopyranose-2-ulose ethylene acetal was dissolved in 150 ml of dry tetrahydrofuran-water (2: 1), and 2 g of p-toluenesulfonic acid monohydrate was added. After the obtained mixture was heated under reflux for 2 hours, the solvent was distilled off under reduced pressure. The obtained syrupy crude product was dissolved in 200 ml of ethyl acetate, washed with 100 ml of saturated saline three times, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 1.1 g of the desired product (Intermediate No. 46). N of this thing
The MR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 1.16
(3H, t, J = 7.6 Hz); 2.35 (2H, q
d, J = 7.6, 1.5 Hz); 3.81 (1H, d,
J = 6.6 Hz); 3.95 (1H, dd, J = 6.
5.12 (1H, t, J = 4.6H)
z); 5.48 (1H, s); 7.03 (1H, dt,
(J = 4.6, 1.5 Hz) The following compounds were synthesized according to Intermediate Synthesis Example 8, and their physical properties are described.

Intermediate No. 47 ¹ H NMR (CDCl ₃ , 400 MHz): 0.90
(3H, t, J = 7.2 Hz); 1.30-1.50
(4H, m); 2.17 (1H, ddd, J = 14.
4,6.8, 1.6 Hz); 2.23 (1H, dd, J)
= 14.4, 6.8 Hz); 3.69 (1H, d, J =
3.86 (1H, dd, J = 6.8,
4.98 (1H, t, J = 4.4H)
z); 5.36 (1H, s); 6.92 (1H, dt,
J = 4.4, 1.6 Hz)

Intermediate Synthesis Example 9 1,6-Anhydro-
Synthesis of 3,4-dideoxy-3-methoxymethyl-β-D-glycero-hex-3-enopyranose-2-ulose (intermediate No. 48) [1] Obtained in Intermediate Synthesis Example 8 [1] above 1,6-
Anhydro-3-bromo-3,4-dideoxy-β-D
1.65 g of glycero-hex-3-enopyranose-2-ulose ethylene acetal was dissolved in 200 ml of dry tetrahydrofuran and cooled to -78 ° C.
5 ml (1.6 N) of n-butyllithium was gradually added thereto, and the mixture was further stirred for 20 minutes. After a large excess of formaldehyde gas was added to the obtained reaction mixture, the temperature was raised to room temperature. After confirming the completion of the reaction by TLC, the precipitate was removed by filtration through Celite (registered trademark). The filtrate is concentrated under reduced pressure, and the resulting syrupy composition product is purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 1,6-anhydro-
3,4-dideoxy-3-hydroxymethyl-β-D-
0.7 g of glycero-hex-3-enopyranose-2-ulose ethylene acetal was obtained. N of this thing
The MR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 2.04
(1H, br.s); 3.73 (2H, m); 4.00
-4.20 (5H, m); 4.17 (1H, dd, J =
4.79 (1H, m); 5.
19 (1H, s); 6.32 (1H, dt, J = 4.
8, 1.2Hz)

The 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-β-D obtained in the above [1]
2 g of p-toluenesulfonic acid monohydrate was added to 150 ml of a methanol solution of 2.8 g of -glycero-hex-3-enopyranose-2-ulose, and the mixture was refluxed for 1 hour. TL
After confirming the disappearance of the raw materials in C, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 0.8 g of the desired product (Intermediate No. 48). Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.40
(3H, s); 3.73 (1H, d, J = 6.8H)
z); 3.89 (1H, dd, J = 6.8, 4.4H
z); 4.07 (1H, br, d, J = 15 Hz);
4.11 (1H, dd, J = 14.4, 1.6 Hz);
5.06 (1H, t, J = 4.4 Hz); 5.36 (1
H, s); 7.20 (1H, dt, J = 4.4, 1.
6) Next, specific synthesis examples of the compound represented by the general formula (I) will be described.

Synthesis Example 1 1,6-anhydro-3,4-
Synthesis of dideoxy-β-D-threo-hex-3-enopyranose (Compound No. 1) Under an inert atmosphere of nitrogen gas at 0 ° C., 500 ml of a suspension of 3.0 g of lithium aluminum hydride in 500 ml of dry diethyl ether was added. 6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2
-50 ml of a dry diethyl ether solution of 20 g of urose
Was gradually added dropwise. Immediately after the addition, return to room temperature
Stirring was continued for minutes. The disappearance of the starting material was confirmed by thin layer chromatography, and a small amount of water was added to inactivate the excess lithium aluminum hydride. After stirring for an additional 30 minutes, the reaction mixture was filtered through celite to remove the precipitate. The precipitate was washed several times with diethyl ether, and the washings were concentrated under reduced pressure together with the filtrate. The precipitated crude crystals were recrystallized from diethyl ether to give the desired product (Compound No. 1)
Was obtained in an amount of 14.5 g. Its NMR analysis values and physical properties are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.73
(1H, dd, J = 6.4, 4.0 Hz); 3.82
(1H, d, J = 6.4 Hz); 4.32 (1H, b
r. s); 4.65 (1H, t, J = 4.0 Hz);
5.51 (1H, t, J = 2.2 Hz); 5.69 (1
H, dt, J = 10.0, 2.2 Hz); 6.09 (1
H, dd, J = 10.0, 4.0 Hz) m. p. 69-71 ° C

Synthesis Example 2 1,6-Anhydro-3,4-
Dideoxy-2-O-isovaleryl-β-D-threo-
Synthesis of Hexo-3-enopyranose (Compound No. 2; isovaleric acid ester of Compound No. 1) At 0 ° C. under an inert atmosphere of nitrogen gas, the 1,6-anhydro-3, 4-dideoxy-β-D
-Threo-hex-3-enopyranose (0.5 g) in a dry pyridine solution (30 ml) was mixed with 0.7% isovaleryl chloride.
g was added slowly. After stirring for about 10 minutes, the ice bath was removed and the mixture was further stirred at room temperature for 2 hours. A small amount of water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl acetate, and 200 ml of saturated saline was dissolved.
And washed three times. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the desired product (compound N).
o. 0.85 g of 2) was obtained as a colorless liquid. Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 0.97
(6H, d, J = 6.9 Hz); 2.12 (1H, qq
tJ = 6.9, 6.9, 6.9 Hz); 2.27 (2
H, d, J = 6.9 Hz); 3.79 (1H, dd, J)
= 6.6, 4.0 Hz); 3.97 (1H, d, J =
4.68 (1H, t, J = 4.0H)
5.53 (1H, br.s); 5.51 (1H,
dt, J = 9.6, 2.0 Hz); 5.63 (1H,
m); 6.19 (1H, ddd, J = 9.6, 4.0,
1.2 Hz) The following compounds were synthesized according to the case of Synthesis Example 2, and their physical properties are described.

Compound No. 3 (crotonate of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 1.95
(3H, dd, J = 6.8, 1.6 Hz); 3.80
(1H, ddd, J = 6.5, 4.2, 1.2 Hz);
3.98 (1H, d, J = 6.5 Hz); 4.69 (1
H, t, J = 4.2 Hz); 5.55 (1H, m);
5.65 (1H, dt, J = 9.2, 2.3 Hz);
5.66 (1H, m); 5.92 (1H, dq, J = 1
6.19 (1H, ddt, J = 5.5, 1.6 Hz);
9.2, 4.2, 1.2 Hz); 7.04 (1H, d)
q, J = 15.5, 6.8 Hz)

Compound No. 4 (cyclohexanoate of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 1.15
-1.30 (3H, m); 1.43 (2H, m);
61 (1H, m); 1.73 (2H, m); 1.90
(2H, m); 2.37 (1H, tt, J = 11.4,
3.3 Hz); 3.76 (1H, ddd, J = 6.5,
4.1, 1.2 Hz); 3.94 (1H, d, J = 6.
4.66 (1H, t, J = 4.1Hz);
5.47 (1H, m); 5.58 (1H, dt, J =
9.7, 2.2 Hz); 5.60 (1H, m); 6.1
7 (1H, ddd, J = 9.7, 3.7, 1.2 Hz)

Compound No. 5 (benzoic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.84
(1H, ddd, J = 6.5, 4.2, 1.1 Hz);
4.03 (1H, d, J = 6.5 Hz); 4.74 (1
H, t, J = 4.2 Hz); 5.74 (2H, m);
5.78 (1H, m); 6.26 (1H, dd, J =
9.2, 4.2 Hz); 7.44 (2H, t, J = 7.
7.57 (1H, tt, J = 7.5, 1.5)
Hz); 8.09 (2H, m) m. p. 116-117 ° C

Compound No. 6 (n-hexanoate of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 6.6 Hz); 1.32 (4H,
m); 1.64 (2H, m); 2.38 (2H, t, J
= 7.7 Hz); 3.80 (1H, m); 3.98 (1
4.68 (1H, t, J = H, d, J = 7.1 Hz);
5.52 (1H, br, s); 5.51
(1H, m); 5.64 (1H, br.s); 6.19
(1H, dd, J = 11.1, 4.8 Hz)

Compound No. 7 (palmitic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 6.8 Hz); 1.25 (24H, b
r. s); 1.60-1.70 (2H, m); 2.38
(2H, dd, J = 7.6, 6.8 Hz); 3.80
(1H, ddd, J = 6.4, 4.0, 1.0 Hz);
3.98 (1H, d, J = 6.4 Hz); 4.69 (1
H, t, J = 4.0 Hz); 5.52 (1H, m);
5.62 (1H, dt, J = 10.0, 2.2 Hz);
5.64 (1H, m); 6.20 (1H, m) m. p. 39-41 ° C. [α] ²⁰ _D = −17.4 (c = 0.402, chloroform)

Compound No. 109 (Compound No. 103
Palmitate _{^{ester) 1 H NMR (CDCl 3,}} 400MHz): 0.88
(3H, t, J = 6.8 Hz); 1.25 (24H, b
r. s); 1.63 (2H, quin, J = 7.2H)
z); 2.35 (2H, t, J = 7.2 Hz); 3.7
2 (2H, m); 4.76 (1H, t, J = 4.4H
z); 4.78 (1H, br.d, J = 4.0 Hz);
5.53 (1H, m); 5.78 (1H, ddd, J =
9.6, 4.0, 2.0 Hz); 6.31 (1H, dd)
d, J = 9.6, 4.4, 0.8 Hz)

Compound No. 8 (oleic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 0.90
(3H, t, J = 7.6 Hz); 1.35-1.23
(20H, m); 1.64 (2H, m); 1.98 (4
H, m); 2.38 (2H, t, J = 7.7 Hz);
3.79 (1H, ddd, J = 6.5, 4.2, 1.5
3.97 (1H, d, J = 6.5 Hz);
68 (1H, t, J = 4.2 Hz); 5.85 (2H,
m); 5.52 (1H, br.s);
dt, J = 9.9, 1.6 Hz); 5.63 (1H,
m); 6.29 (1H, dd, J = 9.9, 4.2H)
z)

Compound No. 9 (acetic acid ester of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 2.14
(3H, s); 3.80 (1H, ddd, J = 6.8,
4.4, 0.8 Hz); 3.98 (1H, d, J = 6.
4.69 (1H, t, J = 4.4 Hz);
5.52 (1H, m); 5.63 (1H, m); 5.6
5 (1H, d, J = 2.8 Hz); 6.20 (1H, d
dt, J = 9, 2, 4.4, 0.8 Hz)

Compound No. 10 (α- of compound No. 1)
Chloroacetic ester) ¹ H NMR (CDCl ₃ , 400 MHz): 3.81
(1H, ddd, J = 6.8, 4.0, 1.0 Hz);
3.97 (1H, d, J = 6.8 Hz); 4.13 (1
H, d, J = 15.2 Hz); 4.17 (1H, d, J)
4.71 (1H, t, J = 4.0H)
z); 5.59 (1H, m); 5.64 (1H, dt,
J = 10.0, 2.2 Hz); 5.67 (1H, t, J)
= 2.2 Hz); 6.25 (1H, ddd, J = 10.
0, 4.0, 1.0 HZ) [α] ²⁰ _D = -43.1 (c = 0.627, chloroform).

Compound No. 11 (O- of compound No. 1)
Acetylsalicylic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 2.36
(3H, s); 3.83 (1H, ddd, J = 6.8,
4.4, 1.6 Hz); 3.98 (1H, d, J = 6.
4.72 (1H, t, J = 4.4Hz);
5.72 (3H, m); 6.24 (1H, ddd, J =
10.8, 4.4, 1.6 Hz); 7.10 (1H, d
d, J = 7.6, 1.2 Hz); 7.31 (1H, t)
d, J = 7.6, 1.2 Hz); 7.56 (1H, t)
d, J = 7.6, 1.2 Hz); 8.08 (1H, d
d, J = 7.6, 1.2 Hz)

Synthesis Example 3 1,6-Anhydro-2-O-
Synthesis of Decanoyl-3,4-dideoxy-β-D-threo-hex-3-enopyranose (Compound No. 12; Decanoate of Compound No. 1) The above synthesis was conducted while stirring under an inert atmosphere of nitrogen gas. Example 1
1,6-anhydro-3,4-dideoxy- obtained in
β-D-threo-hex-3-enopyranose 0.3 g
0.6 g of decanoic acid in 50 ml of a dry methylene chloride solution of
0.97 g of dicyclohexylcarbodiimide and N, N
-Dimethylaminopyridine 28 mg was added. After stirring the reaction mixture for 12 hours at room temperature, the resulting precipitate was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained syrupy crude product was purified by column chromatography on silica gel (ethyl acetate: hexane = 1: 3) to obtain 0.38 g of the desired product (Compound No. 12). Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 0.87
(3H, t, J = 6.8 Hz); 1.26 (12H,
m); 1.64 (2H, quin., J = 7.5H)
z); 2.36 (1H, dt, J = 16.8, 7.5H
z); 2.40 (1H, dt, J = 16.8, 7.5H
z); 3.97 (1H, ddd, J = 6.4, 4.0,
1.0 Hz); 3.98 (1H, d, J = 6.4H)
z); 4.69 (1H, t, J = 4.0 Hz); 5.5
2 (1H, m); 5.63 (1H, dt, J = 9.6,
2.2Hz); 5.65 (1H, m); 6.19 (1
(H, ddd, J = 9.6, 4.0, 1.0 Hz) The following compounds were synthesized according to the case of Synthesis Example 3 above, and their physical properties are described.

Compound No. 13 (6- of compound No. 1)
Bromohexanoate) ¹ H NMR (CDCl ₃ , 400 MHz): 1.49
(2H, tt, J = 8.0, 6.8 Hz); 1.68
(2H, quin. J = 8.0 Hz); 1.88 (2
H, quin. J = 6.8 Hz); 2.41 (2H, t
d, J = 8.0, 1.6 Hz); 3.40 (2H, t,
J = 6.8 Hz); 3.79 (1H, ddd, J = 6.
8, 4.4, 1.6 Hz); 3.97 (1H, d, J =
4.69 (1H, t, J = 4.4H)
5.5) (1H, m); 5.52 (1H, dt,
J = 10.0, 2.0 Hz); 5.64 (1H, m);
6.20 (1H, ddd, J = 10.0, 4.4, 1.
6Hz)

Compound NO. 14 (2- of compound No. 1)
Thiophenecarboxylic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.8, 4.5, 1.0 Hz);
4.02 (1H, d, J = 6.8 Hz); 4.73 (1
H, t, J = 4.5 Hz); 5.69 (1H, m);
5.75 (1H, dt, J = 9.9, 2.3 Hz);
5.77 (1H, m); 6.25 (1H, ddd, J =
9.9, 4.5, 1.0 Hz); 7.11 (1H, d
d, J = 4.8, 3.8 Hz); 7.59 (1H, d
d, J = 4.8, 0.9 Hz); 7.86 (1H, d
d, J = 3.8, 0.9 Hz) m. p. 69-71 ° C

Compound No. 15 (nicotinic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.84
(1H, ddd, J = 6.4, 4.4, 1.2 Hz);
4.02 (1H, d, J = 6.4 Hz); 4.75 (1
H, t, J = 4.4 Hz); 5.74 (2H, m);
5.77 (1H, dt, J = 9.6, 2.4 Hz);
6.29 (1H, ddd, J = 9.6, 4.4, 1.2)
Hz); 7.40 (1H, ddd, J = 8.0, 5.
8.35 (1H, dt, J = 8.
8.79 (1H, dd, J = 5. 0, 1.2 Hz);
9.27 (1H, br.d, J =
1.2 Hz) m. p. 76-81 ° C

Compound No. 16 (p- of compound No. 1)
Chlorobenzoate) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.4, 4.0, 1.2 Hz);
4.02 (1H, d, J = 6.4 Hz); 4.74 (1
H, t, J = 4.0 Hz); 5.72 (1H, m);
5.74 (1H, dt, J = 9.2, 2.4 Hz);
5.76 (1H, m); 6.26 (1H, ddd, J =
9.2, 4.0, 1.2 Hz); 7.41 (2H, d
t, J = 8.8, 2.0 Hz); 8.02 (2H, d
t, J = 8.8, 2.0 Hz) m. p. 57-59 ° C

Compound No. 17 (2- of compound No. 1)
Furan carboxylate) ¹ H NMR (CDCl ₃ , 400 MHz): 3.82
(1H, dd, J = 6.4, 4.4 Hz); 4.02
(1H, d, J = 6.4 Hz); 4.72 (1H, t,
J = 4.4 Hz); 5.71 (1H, m); 5.72
(1H, m); 5.75 (IH, m); 6.25 (1
H, dd, J = 9.6, 4.4 Hz); 6.51 (1
H, dd, J = 3.4, 2.0 Hz): 7.26 (1
H, dd, J = 3.4, 1.0 Hz); 7.59 (1
H, m) m. p. 86-88 ° C

Compound No. 18 (cinnamic ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.8, 4.2, 1.6 Hz);
4.02 (1H, d, J = 6.8 Hz); 4.73 (1
H, t, J = 4.2 Hz); 5.66 (1H, m);
5.71 (1H, dt, J = 10.0, 2.2 Hz);
5.73 (1H, m); 6.24 (1H, ddd, J =
10.0, 4.4, 1.6 Hz); 6.54 (1H,
d, J = 16.0 Hz); 7.39 (3H, m);
53 (2H, m); 7.25 (1H, d, J = 16.0)
Hz) m. p. 147-153 ° C

Compound No. 19 (anthranilic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.8, 4.2, 0.8 Hz);
4.02 (1H, d, J = 6.8 Hz); 4.73 (1
H, t, J = 4.2 Hz); 5.71 (1H, m);
5.75 (2H, m); 6.25 (1H, ddd, J =
10.2, 4.2, 0.8 Hz); 6.66 (1H, d
dd, J = 8.4, 6.8, 1.6 Hz); 6.67.
(1H, br.d, J = 8.4 Hz); 7.28 (1
H, ddd, J = 8.4, 6.8, 1.6 Hz);
94 (1H, dd, J = 8.4, 1.6 Hz) m. p. 95-100 ° C

Compound No. 20 (aratidylic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 7.2 Hz); 1.26 (32H, b
r. s); 1.65 (2H, m); 2.38 (2H,
t, J = 7.8 Hz); 3.80 (1H, ddd, J =
6.4, 4.3, 1.0 Hz); 3.98 (1H, d,
4.69 (1H, t, J = 4.3H);
5.5) (1H, m); 5.52 (1H, dt,
J = 9.6, 2.2 Hz); 5.64 (1H, m);
6.19 (1H, dddd, J = 9.6, 4.3, 1.
2,1.0Hz)

Compound No. 50 (o- of compound No. 1)
Methyl benzoate) ¹ H NMR (CDCl ₃ , 400 MHz): 2.61
(3H, s); 3.83 (1H, m); 4.01 (1
H, d, J = 6.4 Hz); 4.73 (1H, t, J =
4.1Hz); 5.72 (1H, m); 5.76 (1
H, dt, J = 9.5, 2.2 Hz); 5.79 (1
H, m); 6.25 (1H, dd, J = 9.5, 4.1)
Hz); 7.24 (2H, m); 7.40 (1H, t
d, J = 7.4, 1.4 Hz); 7.97 (1H, d
d, J = 8.3, 1.4 Hz)

Synthesis Example 4 1,6-Anhydro-3,4-
Dideoxy-2-O-methoxycarbonyl-β-D-threo-hex-3-enopyranose (Compound No. 2
1; Compound No. 1 Synthesis of 1,6-anhydro-3,1 under an inert atmosphere of nitrogen gas
0.33 g of methyl chlorocarbonate was gradually added to 30 ml of a dry pyridine solution of 0.3 g of 4-dideoxy-β-D-threo-hex-3-enopyranose. The reaction mixture was stirred at room temperature for 12 hours, 0.33 g of methyl chlorocarbonate was further added, and the mixture was stirred for 30 minutes. After inactivating excess methylchlorocarbonate by adding a small amount of water, the solvent was distilled off under reduced pressure. Ethyl acetate 200 in the residue
Then, the mixture was washed three times with 200 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting syrupy crude product was subjected to silica gel column chromatography (ethyl acetate-hexane =
1: 3), and the target compound (Compound No. 21) was purified in 0.1.
33 g were obtained. Its NMR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.80
(1H, m); 3.81 (3H, s); 3.96 (1
H, d, J = 6.8 Hz); 4.70 (1H, t, J =
5.37 (1H, m); 5.68 (1
H, dt, J = 10.0, 2.0 Hz); 5.71 (1
H, t, J = 2.2 Hz); 6.23 (1H, ddd,
J = 10.0, 4.4, 1.2 Hz) The following compounds were synthesized in the same manner as in Synthesis Example 4 above, and their physical properties are described.

Compound No. 22 (phenyl carbonate ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.85
(1H, ddd, J = 6.8, 4.3, 1.3 Hz);
4.02 (1H, d, J = 6.8 Hz); 4.74 (1
H, t, J = 4.3 Hz); 5.47 (1H, m);
5.77 (1H, dt, J = 9.3, 2.4 Hz);
5.79 (1H, m); 6.29 (1H, ddt, J =
9.3, 4.3, 1.3 Hz); 7.20 (2H,
m); 7.26 (1H, m); 7.39 (2H, m) m. p. 98-99 ° C

Compound No. 26 (phenylthiocarbonate ester of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 3.86
(1H, ddd, J = 6.8, 4.0, 1.0 Hz);
4.05 (1H, d, J = 6.8 Hz); 4.76 (1
H, t, J = 4.0 Hz); 5.84 (1H, dt, J)
= 10.0, 2.4 Hz); 5.86 (1H, m);
6.05 (1H, m); 6.31 (1H, ddd, J =
10.0, 4.0, 1.0 Hz); 7.31 (2H,
m); 7.30 (1H, tt, J = 7.6, 1.1H)
z); 7.42 (2H, tt, J = 76, 2.2 Hz)

Synthesis Example 5 1,6-Anhydro-3,4-
Dideoxy-2-O-phenylcarbamoyl-β-D-
Threo-hex-3-enopyranose (Compound No. 2
Compound No. 3; 1 phenyl carbamate)
Synthesis of 1,6-anhydro-3, under an inert atmosphere of nitrogen gas
0.56 g of phenyl isocyanate was added to 30 ml of a dry toluene solution of 0.3 g of 4-dideoxy-β-D-threo-hex-3-enopyranose at room temperature. Further, 0.1 ml of triethylamine was added, and the reaction mixture was refluxed for 2 hours while heating. After confirming the completion of the reaction by thin-layer chromatography, the solvent was immediately distilled off under reduced pressure to obtain a syrupy crude product. This was subjected to chromatography (ethyl acetate: hexane = 1: 3) on silica gel to obtain 0.5 g of the desired product (Compound No. 23). Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.83
(1H, ddd, J = 7.6, 5.2, 1.9 Hz);
3.99 (1H, d, J = 7.6 Hz); 4.73 (1
H, t, J = 5.2, Hz); 5.57 (1H, m);
5.71 (1H, m); 5.73 (1H, dt, J = 1
0.0, 2.7 Hz); 6.23 (1H, ddd, J =
10.0, 5.2, 1.9 Hz); 6.83 (1H, b
r. s); 7.08 (1H, tt, J = 7.6, 1.0
Hz); 7.32 (2H, t, J = 7.6 Hz);
37 (2H, d, J = 7.6 Hz) m. p. 107-109 ° C

Synthesis Example 6 1,6-Anhydro-3,4-
Dideoxy-2-O-methylthiocarbamoyl-β-D
-Threo-hex-3-enopyranose (Compound No.
Compound No. 24; Synthesis of 1,6-anhydro-3,1 under an inert atmosphere of nitrogen gas
To 30 ml of a dry toluene solution of 0.35 g of 4-dideoxy-β-D-threo-hex-3-enopyranose was added 0.4 g of methylthioisocyanate, and then sodium hydride (60% dispersion in mineral oil, 1. 3 eq.) Were added slowly. After confirming that the generation of hydrogen was completed (5-10 minutes), stirring was further continued for 1 hour. After confirming the completion of the reaction by thin-layer chromatography, a small amount of water was added to inactivate excess sodium hydride, and the resulting precipitate was removed by filtration through Celite-anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 0.45 g of the desired product (Compound No. 24). Was. Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 2.92
(0.9H, d, J = 4.6 Hz); 3.07 (2.1
H, d, J = 4.6 Hz); 3.79 (1H, m);
3.94 (0.7H, d, J = 6.5Hz); 3.97
(0.3H, d, J = 6.5Hz); 4.70 (0.7
H, t, J = 3.7 Hz); 4.71 (0.3 H, t,
J = 3.7 Hz); 5.72 (2H, m); 6.19
(2H, m); 6.61 (0.7H, br.s);
79 (0.3H, br.s) The following compound was synthesized in the same manner as in the case of Synthesis Example 6, and the physical properties are described.

Compound No. 25 (N- of compound No. 1)
tert-butyl carbamate) ¹ H NMR (CDCl ₃ , 400 MHz): 1.31
(9H, s); 3.79 (1H, ddd, J = 6.4,
4.4, 1.5 Hz); 3.95 (1H, d, J = 6.
4.68 (1H, t, J = 4.4 Hz);
4.87 (1H, br.s); 5.41 (1H, br.
s); 5.65 (1H, m); 5.66 (1H, dt,
J = 9.6, 2.2 Hz); 6.16 (1H, ddd,
J = 9.6, 4.4, 1.5 Hz) m. p. 113-115 ° C

Synthesis Example 7 1,6-Anhydro-3,4-
Synthesis of dideoxy-2-C-vinyl-β-D-threo-hex-3-enopyranose (Compound No. 27) 1,6-Anhydro-3,4 stirred at 0 ° C. under an inert atmosphere of nitrogen gas 9.5 ml (1 mol) of vinylmagnesium bromide were gradually added to 50 ml of a dry tetrahydrofuran solution of 1 g of -dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose. After 30 minutes, the ice bath was removed and stirring continued at room temperature for another 30 minutes. After confirming the completion of the reaction by thin layer chromatography, a small amount of water was added to inactivate the excess Grignard reagent, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl acetate, and 200 ml of saturated saline was dissolved.
After washing three times with 1 l, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting syrupy product was purified by column chromatography on silica gel (ethyl acetate: hexane = 1: 2) to give the desired product (Compound No. 27) in 0.1%. 9 g were obtained. NM of this thing
The analytical values of R are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.73
(1H, dd, J = 6.4, 3.9 Hz); 3.82
(1H, d, J = 6.4 Hz); 4.68 (1H, t,
J = 3.9 Hz); 5.19 (1H, br.s);
4. 26 (1H, dt, J = 10.5, 1.3 Hz);
36 (1H, dt, J = 17.7, 1.3 Hz);
53 (1H, dt, J = 9.4, 1.3 Hz); 5.9
2 (1H, ddd, J = 17.7, 10.5, 1.0H
z); 6.09 (1H, dd, J = 9.4, 3.9H)
z) The following compounds were synthesized according to the case of Synthesis Example 7, and the physical properties are described.

Compound No. 28 ¹ H NMR (CDCl ₃ , 400 MHz): 1.26
(3H, s): 3.69 (1H, dd, J = 7.0,
4.6 Hz); 3.76 (1H, d, J = 7.0H)
z); 4.62 (1H, t, J = 4.6 Hz); 5.1
7 (1H, d, J = 2.2 Hz); 5.67 (1H, d
d, J = 10.0, 2.2 Hz); 5.94 (1H, d
d, J = 10.0, 4.6 Hz)

Compound No. _{^{29 1 H NMR (CDCl 3,}} 400MHz): 2.69
(1H, s); 3.76 (1H, dd, J = 6.8,
3.82 (1H, d, J = 6.8H)
z); 4.73 (1H, t, J = 4.4 Hz); 5.4
9 (1H, d, J = 2.0 Hz); 5.75 (1H, d
d, J = 9.8, 2.0 Hz); 6.12 (1H, d
d, J = 9.8, 4.4 Hz) m. p. 64-67 ° C. [α] ²⁰ _D = -214.8 (c = 0.433, chloroform)

Compound No. 30 ¹ H NMR (CDCl ₃ , 400 MHz): 0.90
(3H, t, J = 7.0 Hz); 1.35-1.50
(4H, m) 1.60-1.75 (2H, m); 3.7
0 (1H, dd, J = 6.8, 4.4 Hz); 3.77
(1H, d, J = 6.8 Hz); 4.64 (1H, t,
J = 4.4 Hz); 5.22 (1 H, d, J = 2.0 H)
z); 5.61 (1H, dd, J = 10.0, 2.0H
z); 6.00 (1H, dd, J = 10.0, 4.4H
z) m. p. 31-33 ° C

Compound No. 31 ¹ H NMR (CDCl ₃ , 400 MHz): 0.97
(3H, t, J = 7.2 Hz); 1.55 (2H, si
x, J = 7.2 Hz); 2.23 (2H, t, J = 7.
2.26 (1H, br.s); 3.74 (1
H, dd, J = 6.8, 4.4 Hz); 3.80 (1
H, d, J = 6.8 Hz); 4.71 (1H, t, J =
5.44 (1H, d, J = 2.4H)
z); 5.74 (1H, dd, J = 10.0, 2.4H
z); 6.05 (1H, dd, J = 10.0, 4.4H
z) m. p. 43-46 ° C

Synthesis Example 8 2-O-acetyl-1,6-anhydro-3,4-dideoxy-2-C-methyl-β-
D-threo-hex-3-enopyranose (compound N
o. Synthesis of 32) Drying 0.3 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose stirred at 0 ° C. under an inert atmosphere of nitrogen gas. To 30 ml of the tetrahydrofuran solution was slowly added 2.4 ml (1.5 mol) of methyllithium, and after confirming the completion of the reaction by thin-layer chromatography, 0.25 ml of acetyl chloride was added. The ice bath was removed, the reaction solution was returned to room temperature, and stirring was further continued for 1 hour. The solvent was distilled off under reduced pressure, and 200 ml of ethyl acetate was added to the residue. After washing three times with 200 ml of saturated saline, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate-hexane = 1: 5) to obtain 0.29 g of the desired product (Compound No. 32). Was. Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 1.59
(3H, s); 2.05 (3H, s); 3.76 (1
H, dd, J = 6.8, 4.4 Hz); 3.89 (1
H, d, J = 6.8 Hz); 4.63 (1H, t, J =
5.78 (1H, dd, J = 9.6, 4.4 Hz);
5.89 (1H, d, J = 1.6H)
z); 6.06 (1H, dd, J = 9.6, 4.4H)
z) [α] ²⁰ _D = -114.7 (c = 0.654, chloroform) The following compounds were synthesized in the same manner as in the case of Synthesis Example 8, and the physical properties are described.

Compound No. 33 ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 7.2 Hz); 1.25 (24H, b
r. s); 1.57 (2H, m); 1.59 (3H,
s); 2.29 (2H, td, J = 8.0, 1.0H
z); 3.76 (1H, dd, J = 6.4, 4.4H
z); 3.87 (1H, d, J = 6.4 Hz); 4.6
2 (1H, t, J = 4.4 Hz); 5.77 (1H, d
d, J = 9.6, 2.0 Hz); 5.90 (1H, d,
J = 2.0 Hz); 6.06 (1H, dd, J = 9.
6,4.4Hz)

Synthesis Example 9 1,6-Anhydro-3,4-
Synthesis of dideoxy-β-D-erythro-hex-3-enopyranose (Compound No. 103) (1) Synthesis Example 1 at room temperature under an inert atmosphere of nitrogen gas
1,6-anhydro-3,4-dideoxy- obtained in
To 50 ml of a dry pyridine solution of 5 g of β-D-threo-hex-3-enopyranose was added 15 g of tosyl chloride. After stirring for 12 hours, add a small amount of water and add 300m
Extracted with 1 liter of toluene. After washing once with 200 ml of 1N hydrochloric acid, it was washed three times with 200 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the resulting syrupy crude product was purified by column chromatography on silica gel (ethyl acetate: hexane = 1: 1) to give 1,6-anhydro-3,4-
Dideoxy-2-O- (p-toluene) sulfonyl-β
-D-threo-hex-3-enopyranose (compound N
o. 46) was obtained in an amount of 10.5 g. Its NMR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.45
(3H, s); 3.76 (1H, ddd, J = 6.8,
4.0, 1.2 Hz); 3.94 (1H, d, J = 6.
4.65 (1H, t, J = 4.0 Hz);
5.22 (1H, m); 5.45 (1H, t, J = 2.
5.52 (1H, dt, J = 10.4, 2. 4 Hz);
4.19); 6.19 (1H, ddd, J = 10.4,
4.0, 1.2 Hz); 7.35 (2H, br.d, J
= 8.4 Hz); 7.83 (2H, dt, J = 8.4,
2.0 Hz) m. p. 81-83 ° C

(2) 10.5 g of 1,6-anhydro-3,4-dideoxy-2-O-
(P-Toluene) sulfonyl-β-D-threo-hex-3-enopyranose was dissolved in 100 ml of dry dimethylformamide, and 6 g of sodium benzoate was added.
The mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and 20
0 ml of water was added and extracted with 300 ml of chloroform. The organic layer was washed once with 200 ml of saturated aqueous sodium hydrogen carbonate, twice with 200 ml of saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, 100 ml of the obtained syrup-like crude product was added.
Was dissolved in dry methanol, and 2 ml of a methanol solution of sodium methoxide (28 wt.%) Was added, followed by stirring at room temperature for 25 minutes. The reaction solution was neutralized with a 20% aqueous citric acid solution, and then filtered through celite to remove a precipitate. The filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification in 2) was performed to obtain the target compound (Compound No. 103) in 1.1.
g was obtained. Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.50
(1H, br.d, J = 3.6 Hz); 3.64 (2
4.69 (1H, ddd, J = 5.0, 4.H).
5.53 (1H, t, J = 1.8H)
z); 5.82 (1H, ddd, J = 9.6, 4.0,
1.819); 6.19 (1H, ddd, J = 9.6,
5.0, 0.8 Hz) m. p. 50-54 ° C

Synthesis Example 10 1,6-Anhydro-3,4
Synthesis of -Dideoxy-2-O-methyl-β-D-threo-hex-3-enopyranose (Compound No. 41) Under an inert atmosphere of nitrogen gas, sodium hydride (60% dispersion in mineral oil, 1.3 equivalents) in 30 ml of dry tetrahydrofuran solution.
0.3 g of 4-dideoxy-β-D-threo-hex-3-enopyranose was slowly added. After stirring for 15 minutes, 0.45 ml of methyl iodide was added and the reaction was stirred at room temperature for 12 hours. Excess sodium hydride was inactivated by adding a small amount of water and concentrated under reduced pressure. 200 ml of ethyl acetate was added to the obtained syrup-like crude product, washed with 200 ml of saturated saline three times, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup-like product was purified by column chromatography on silica gel (ethyl acetate: hexane = 2: 3) to obtain the desired product (Compound No. 41) in 0.1%. 25 g were obtained. Its NMR analysis values are as follows. _{^{1 H NMR (CDCl 3, 400MHz}} ): 3.44
(3H, s); 3.74 (1H, ddd, J = 6.7,
4.1, 1.3 Hz); 3.91 (1H, d, J = 6.
4.07 (1H, m); 4.62 (1H,
5.61 (1H, t, J = 2, t, J = 4.1 Hz);
5.72 (1H, dt, J = 9.8, 2.2)
Hz); 6.09 (1H, ddd, J = 9.8, 4.
(1, 1.3 Hz) The following compounds were synthesized according to the case of Synthesis Example 10, and the physical properties are described.

Compound No. 40 (n- of compound No. 1)
Butyl ether) ¹ H NMR (CDCl ₃ , 400 MHz): 0.92
(3H, t, J = 7.2 Hz); 1.39 (2H,
m); 1.60 (2H, m); 3.57 (1H, dt,
J = 9.2, 6.8 Hz); 3.60 (1H, dt, J
= 9.2, 6.8 Hz); 3.77 (1H, ddd, J)
= 6.8, 4.0, 1.2 Hz); 3.97 (1H,
d, J = 6.8 Hz); 4.17 (1H, m); 4.6
3 (1H, t, J = 4.0 Hz); 5.62 (1H,
t, J = 2.2 Hz); 5.72 (1H, dt, J =
9.6, 2.2 Hz); 6.08 (1H, ddd, J =
9.6, 4.0, 1.2 Hz) Compound No. 48 (benzyl ether of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 3.78
(1H, ddd, J = 6.4, 4.0, 1.2 Hz);
3.98 (1H, d, J = 6.4 Hz); 4.28 (1
H, m); 4.63 (1H, t, J = 4.0 Hz);
4.66 (1H, d, J = 12.0 Hz); 4.70
(1H, d, J = 12.0 Hz); 5.56 (1H,
5.71 (1H, dt, J = 1)
0.0, 2.4 Hz); 6.10 (1H, ddd, J =
10.0, 4.0, 1.2 Hz); 7.29 (1H, t
t, J = 6.8, 2.0 Hz); 7.34 (2H,
m); 7.38 (2H, m)

Synthesis Example 11 1,6-Anhydro-3,4
Synthesis of -dideoxy-2-O- (16-hydroxy) hexadecanoyl-β-D-threo-hex-3-enopyranose (Compound No. 49) 1 g of 16-hydroxyhexadecane under an inert atmosphere of nitrogen gas A solution of the acid, 1.1 g of tert-butyldimethylsilyl chloride and 0.75 g of imidazole in 50 ml of dry tetrahydrofuran was stirred at room temperature for 12 hours. After evaporating the solvent under reduced pressure, 200 ml of ethyl acetate was added, and the mixture was washed three times with 200 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup-like product. 40m here
l of diethyl ether, 30 ml of methanol and 30
ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, 200 ml of ethyl acetate was added, and the mixture was washed once with 200 ml of saturated sodium hydrogen carbonate and twice with 200 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup-like product. This was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification in 1) gave 1.4 g of 16-tert-butyldimethylsilyloxyhexadecanoic acid.

The 16-tert-butyldimethylsilyloxyhexadecanoic acid obtained in the above reaction and the compound No.
The condensation reaction with 1 was carried out according to Synthesis Example 3 above. After post-treatment in a conventional manner, purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 7). This is dissolved in 50 ml of dry tetrahydrofuran, and 1N
Of tetrabutylammonium fluoride in tetrahydrofuran was added at room temperature, and the mixture was stirred for 12 hours.
After evaporating the solvent under reduced pressure, 200 ml of ethyl acetate was added, and the mixture was washed twice with 200 ml of saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off again under reduced pressure to obtain a syrup-like product. This was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 0.59 g of the desired product (Compound No. 49). Its NMR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.20
-1.37 (22H, m); 1.57 (2H, qui)
n. , J = 7.0 Hz); 1.64 (2H, qui)
n. , J = 7.0 Hz); 2.38 (2H, t, J =
2.64 (2H, td, J = 5.6, 7.4 Hz);
5.6 Hz); 3.80 (1H, ddd, J = 6.6,
4.1, 1.1 Hz); 3.98 (1H, d, J = 6.
4.69 (1H, t, J = 4.1 Hz);
5.52 (1H, m); 5.62 (1H, dt, J =
9.5, 2.1 Hz); 5.64 (1H, m); 6.2
0 (1H, ddt, J = 9.5, 4.1, 1.1 Hz) The following compounds were synthesized according to Synthesis Example 1 or 2, and their physical property values are described.

1,6-Anhydro-3,4-dideoxy-3-methyl-β-D-threo-hex-3-enopyranose (Compound No. 51) ¹ H NMR (CDCl ₃ , 400 MHz): 1.72
(3H, m); 2.03 (1H, d, J = 12.0H
z); 3.71 (1H, dd, J = 6.4, 4.4H)
z); 3.78 (1H, d, J = 6.4 Hz); 4.1
1 (1H, m); 4.60 (1H, t, J = 44H
z); 5.51 (1H, d, J = 2.8 Hz); 5.8
0 (1H, dd, J = 4, 4, 1.6 Hz) m. p. 62.5-64 ° C

1,6-Anhydro-3,4-dideoxy-3-ethyl-β-D-threo-hex-3-enopyranose (Compound No. 95) ¹ H NMR (CDCl ₃ , 400 MHz): 1.02
(3H, t, J = 7.2 Hz); 1.57 (1H, b
r. s); 2.12 (2H, m); 3.73 (1H, d
d, J = 6.0, 4.4 Hz); 3.78 (1H, d,
J = 6.0 Hz); 4.21 (1H, d, J = 3.2H)
z); 4.65 (1H, t, J = 4.4 Hz); 5.5
3 (1H, d, J = 3.2 Hz); 5.80 (1H,
m) m. p. 75-76 ° C

1,6-anhydro-3-butyl-3,4
-Dideoxy-β-D-threo-hex-3-enopyranose (Compound No. 97) ¹ H NMR (CDCl ₃ , 400 MHz): 0.94
(3H, t, J = 7.2 Hz); 1.41 (4H,
m); 1.65 (1H, br.s); 2.06 (1H, br.s).
ddd, J = 15.0, 9.6, 6.0 Hz); 2.1
8 (1H, ddd, J = 15.0, 8.8, 5.6H
z); 3.72 (1H, dd, J = 6.8, 4.0H
z); 3.78 (1H, d, J = 6.8 Hz); 4.1
9 (1H, d, J = 2.8 Hz); 4.63 (1H,
5.52 (1H, d, J = 2.t, J = 4.0 Hz);
5.79 (1H, br.d, J = 5Hz) m. p. 43-44 ° C

1,6-anhydro-3,4-dideoxy-3-methoxymethyl-β-D-threo-hex-3-
Enopyranose (Compound No. 96) ¹ H NMR (CDCl ₃ , 400 MHz): 3.35
(3H, s); 3.75 (1H, dd, J = 6.8,
3.83 (1H, d, J = 6.8H)
z); 3.91 (1H, br.d, J = 13 Hz);
4.01 (1H, br.d, J = 13 Hz); 4.32
(1H, br, d, J = 2 Hz); 4.70 (1H,
5.53 (1H, d, J = 2.t, J = 4.4 Hz);
8 Hz); 6.09 (1H, m) m. p. 53-56 ° C

Compound No. 98 ¹ H NMR (CDCl ₃ , 400 MHz): 1.63
(3H, s); 3.72 (1H, dd, J = 5.6,
4.4Hz); 3.92 (1H, d, J = 5.6H)
z); 4.61 (1H, t, J = 4.4 Hz); 5.6
0 (1H, br.s); 5.68 (1H, d, J = 2.
5.90 (1H, m); 6.46 (1H, d)
d, J = 3.6, 2.0 Hz); 7.21 (1H, d,
J = 3.6 Hz); 7.54 (1H, s)

Compound No. 99 ¹ H NMR (CDCl ₃ , 400 MHz): 2.85
(1H, s); 3.82 (1H, dd, J = 6.8,
3.94); 3.94 (1H, d, J = 6.8H)
z); 4.76 (1H, t, J = 4.3 Hz); 6.0
1 (1H, dd, J = 9.7, 2.0 Hz); 6.18
(1H, d, J = 2.0 Hz); 6.27 (1H, d
d, J = 9.7, 4.3 Hz); 6.51 (1H, d
d, J = 3.3, 1.3 Hz); 7.23 (1H, d,
J = 3.3 Hz); 7.58 (1H, br.s)

Compound No. 100 ¹ H NMR (CDCl ₃ , 400 MHz): 1.57
(3H, s); 3.66 (1H, dd, J = 5.6,
3.83 (1H, d, J = 5.6H)
4.06 (1H, br.s); 4.50 (1H,
t, J = 4.4 Hz); 4.54 (1H, d, J = 1)
3.05); 4.59 (1H, d, J = 13.0H)
z); 5.40 (1H, d, J = 2.4 Hz); 5.7
2 (1H, m); 6.28 (1H, dd, J = 3.0,
6.30 (1H, d, J = 3.0H)
z); 7.36 (1H, s)

Compound No. 101 ¹ H NMR (CDCl ₃ , 400 MHz): 3.77
(1H, ddd, J = 7.2, 4.4, 1.2 Hz);
3.96 (1H, d, J = 7.2 Hz); 4.31 (1
H, m); 4.60 (1H, d, J = 13.2 Hz);
4.63 (1H, m); 4.64 (1H, d, J = 1
3.50); 5.50 (1H, t, J = 2.4H)
z); 5.64 (1H, dt, J = 9.6, 2.4H)
z); 6.09 (1H, ddd, J = 9.6, 4.4,
6.36 (2H, m); 7.41 (1
H, dd, J = 1.6, 0.8 Hz)

Compound No. 102 ¹ H NMR (CDCl ₃ , 400 MHz): 2.92
(1H, s); 3.78 (1H, dd, J = 6.8,
3.95 (1H, d, J = 6.8H)
z); 4.17 (1H, dt, J = 4.4 Hz);
73 (1H, d, J = 12.6 Hz); 4.80 (1
H, d, J = 12.6 Hz); 5.57 (1H, d, J)
= 2.0 Hz); 5.70 (1H, dd, J = 9.6,
2.0 Hz); 6.12 (1H, dd, J = 9.6,
4.4Hz); 6.33 (2H, m); 7.41 (1
H, m) Next, the enopyranose derivatives represented by the general formula (I-1) or (I-2) are exemplified in Tables 3 to 11.

[0125]

[Table 3]

[0126]

[Table 4]

[0127]

[Table 5]

[0128]

[Table 6]

[0129]

[Table 7]

[0130]

[Table 8]

[0131]

[Table 9]

[0132]

[Table 10]

[0133]

[Table 11]

Next, it is shown that the enopyranose derivative represented by the above general formula (I) or a salt thereof is useful as an active ingredient of an immunological function inhibitor. (Pharmacological test) (1) Inhibitory effect of collagen-induced arthritis 4 to 6-week-old male DBA / 1JNCrj mice in one group 4
Bovine collagen type II (manufactured by Collagen Technology Workshop, product No. K41) (3 mg / ml) emulsified with an equal volume of complete Freund's adjuvant (ICN Immunobiologicals, product No. 642851) Was injected intradermally at the ridge of the mouse (150 μg /
0.1 ml / mouse) to induce collagen arthritis.
The arthritis intensity was scored and evaluated as follows (0 to 3 points per limb, 12 points maximum for limbs). O point No change 1 point Weak finger swelling and weak erythema 2 points Weak swelling and erythema 3 points Strong swelling and erythema, or with bone deformation The basic operation of the above test was performed according to The Journal of Immunology (The Journal of Immunology). Journal of Immun
(vol.) 140, 1477-1484, (19)
1988).

(A) Inhibitory effect of collagen arthritis onset On day 18 after antigen inoculation, administration of the compound of the above general formula (I) (50 mg / kg) was started. It was administered daily for weeks, and the state of arthritis was observed. In addition, it tested similarly using physiological saline as a control. The result is shown in FIG.

(2) Effects on Various Cultured Cells (a) Effects on Immature Transformation Reaction Using Mouse Thymocytes Using BALB / c mouse thymocytes, concanavalin A (hereinafter abbreviated as ConA; Vector Laboratories) The effect of the compound of the general formula (I) on the lymphocyte blastogenesis response to the stimulation by the product No. L-1000) was examined. That is, 4 × 10 ⁵ thymocytes were converted to ConA (5 μg /
ml) and an RPMI 1640 solution containing 10% fetal calf serum together with the compound of the formula (I) (hereinafter 10% FCS-R).
48) in a 96-well microplate
Culture for 5 hours (5% CO ₂ in an incubator, 37
° C). Then, 0.5 μCi of ³ H-thymidine (hereinafter referred to as ³
H-TdR) was added thereto, and after culturing for further 4 hours, the cells were collected using a cell harvester, and the radioactivity (dpm) of ³ H-TdR incorporated into the cells was measured. The measured uptake of ³ H-TdR into the cells was used as an indicator of the thymic cell blastogenesis reaction, and radiation at each concentration (0.001 to 1000 μg / ml) of the compound of general formula (I) was measured. The activity value was compared with the control value of ConA treatment alone, and IC5
Zero values were calculated and the results are shown in Tables 12 and 13.
In Tables 12 and 13, the results of thymocytes are shown as (a). For these basic operations, the cell immunity experiment operation method, pages 144 to 146 (translated by Katsuyuki Imai et al., Published by Rikensha, 1982) was referred to.

(B) Effect on mouse lymphocyte mixed culture reaction Effect of compound of general formula (I) on bidirectional lymphocyte mixed culture reaction using BALB / c and C57BL / 6 mouse spleen cells It was investigated. That is, 5 × 10 ⁵ spleen cells of both mice were mixed and cultured in a 96-well microplate for 48 hours in a 10% FCS-RPMI solution together with the compound of the general formula (I) (5 in an incubator). % _CO 2, 37 ℃). Then, 0.5 μCi of ³
After adding H-TdR and further culturing for 16 to 18 hours, cells were collected with a cell harvester and incorporated into the cells.
The radioactivity (dpm) of ³ H-TdR was measured. The measured uptake of ³ H-TdR into cells is used as an indicator of the mixed lymphocyte reaction, and the radioactivity at each concentration (0.001 to 1000 μg / ml) of the compound of general formula (I) is measured. Was compared with an untreated control value to calculate an IC50 value, and the results are shown in Tables 12 and 13. This Table 12
And in Table 13, the result of the lymphocyte mixed culture reaction is shown as (b). For these basic operations, the cell immunity experiment operation method, pp. 147 to 149 (translated by Katsuyuki Imai et al., Published by Rigaku Corporation, 1982) was referred to.

(C) Effect on mouse bone marrow cells Bone marrow cells were excised from the femur of BALB / c mice.
The cells suspended in the 0% FCS-RPMI solution were suspended on a 10 cm plastic Petri dish and allowed to stand (5% CO _{2 in} an incubator at 37 ° C.). Two hours later, only floating cells were collected, and adherent cells were removed. Suspension cells 1x
10 ⁵ cells were combined with a 20% culture supernatant of L929 fibroblast cells and a compound of general formula (I) in 10% FCS-RPM.
The solution I was cultured in a 96-well microplate for 48 hours (5% CO ₂ , 37 ° C. in an incubator). Thereafter, 0.5 μCi of ³ H-TdR was added, and after further culturing for 4 hours, cells were collected with a cell harvester, and the radioactivity (dpm) of ³ H-TdR incorporated into the cells was measured. The measured uptake of ³ H-TdR into cells was used as an index of the proliferation reaction of bone marrow cells, and the concentration of the compound of general formula (I) (0.001 to 1000 μg /
ml) was compared with the control value of the L929 culture supernatant alone, and the IC50 value was calculated.
2 and Table 13. In Tables 12 and 13, the results for bone marrow cells are shown as (c). These basic operations are described in the Japanese Society of Biochemistry
Vol. 266-270 (Tokyo Kagaku Doujin Publishing, 1986)
Year).

[0139]

[Table 12]

[0140]

[Table 13]

(D) Effect on Mouse Spleen Cell Antibody Production Induced by stimulation of LPS (lipopolysaccharide; Wako Pure Chemical Industries, product No. 520.02051) and IL4 (interleukin 4) using mouse spleen B cells. I
The effect of the compound of the general formula (I) on the production of gGl, IgM and IgE antibodies was examined. That is, BALB / c
Mouse spleen cells were treated with mouse anti-Thy-1 antibody (obtained from Chiba University School of Medicine) and rabbit complement (manufactured by Cedarane Co., product No. 3051) to remove T cells and spleen B cells 3 × 10 ⁵ 10 μg / ml of LPS and mouse recombinant IL4 (manufactured by Dienzyme, product no.
MIL-4C) was cultured for 7 days in a 96-well microplate in a 10% FCS-RPMI solution together with 100 U / ml of each of the compounds of the general formula (I) (0.001 to 1000 μg / ml) (in an incubator, 5% CO ₂ ,
37 ° C).

The basic operation is described in The Journal of Immunology, Vol. 136, p.
(1986). The amount of each antibody in the cell culture supernatant thus obtained was measured by an enzyme immunoassay as described below. First, a rabbit anti-mouse IgG1 antibody (manufactured by Kappel, product no.
36243) 1 μg / ml or goat anti-mouse IgM antibody (Kappel, product No. 0611-0201) 1
μg / ml, rat anti-mouse IgE monoclonal antibody (manufactured by Experimental Immunology, product no.
LO-ME-2) was adsorbed at 10 μg / ml (50 μl / well, room temperature, 60 minutes), and then 10 mM sodium phosphate buffered saline containing 0.1% bovine serum albumin (p.
H7.2) blocked non-specific binding (room temperature, 60 minutes). Next, 50 μl / well of the above cell culture supernatant or a dilution thereof was added, reacted at room temperature for 60 minutes, and further diluted 1000-fold with an alkaline phosphatase-labeled rabbit anti-mouse IgG1 antibody (manufactured by Zymet, product No.
61-0122), 2000-fold diluted alkaline phosphatase-labeled rabbit anti-mouse IgM antibody (manufactured by Zymet, product No. 61-6822) or 500-fold diluted alkaline phosphatase-labeled sheep anti-mouse IgE antibody (manufactured by Binding Site, product No. 61-0122) .PA-28
4) was added at 50 μl / well, and reacted at room temperature for 60 minutes. 10% diethanolamine buffer containing paranitrophenyl phosphate as enzyme substrate (pH
9.8) 100 μl / well was reacted, and the absorbance at 405 nm was measured. The amount of each antibody was calculated from the calibration curve of each standard antibody, and the IC50 value of the effect of the compound of the general formula (I) on antibody production was determined using the value in the absence of the compound of the general formula (I) as a control value. The results are shown in Tables 14 and 15 together with the results of the effects on the mouse bone marrow cells. In Tables 14 and 15, the IC50 value of the effect on antibody production is shown as each antibody, that is, IgG1, IgM and IgE, and the result of the mouse bone marrow cells described above is shown as (c).

[0143]

[Table 14]

[0144]

[Table 15]

(Toxicity test) DBA1 / J mice, 6 weeks old, male, 4 mice were treated as a group, and the compound of the formula (I) (5
0 mg / kg) was administered once daily intraperitoneally or orally for 4 weeks, and the body weight change and the number of deaths were examined. As a result, there was no noticeable weight change and no deaths occurred. Therefore,
The compound of formula (I) has an LD ₅₀ value of at least 50.
mg / kg.

The enopyranose derivative represented by the general formula (1) or a salt thereof also has an anti-inflammatory effect, and the test examples are described below. (Anti-inflammatory action test) An anti-inflammatory action test was carried out using the carrageenan-induced paw edema method widely used for evaluating the effectiveness of general anti-inflammatory drugs (NSAIDs). 0.1 ml of a 1% λ-carrageenin solution was injected into the sole of the right foot of an SD male rat (6 weeks old), and three hours later, the sole volume of both feet was measured and the volume difference between the right and left sides was edema. Of the degree. The test compound is 1 ml / 100 g 1 hour before carrageenin administration.
(Body weight) orally. The control group received the same amount of physiological saline alone. Table 16 shows the results. As is clear from Table 16, the test compound showed a statistically significant inhibitory effect on carrageenan-induced paw edema, confirming its effectiveness as an anti-inflammatory agent.

[0147]

[Table 16]

When the enopyranose derivative represented by the above general formula (I) or a salt thereof is used as an active ingredient of an immunosuppressive agent, it cannot be unconditionally specified due to a difference in administration conditions. 5000 mg, administered orally or parenterally. The drug can be administered by oral, intravenous, intramuscular, cutaneous route, mucosal route and the like. Dosage forms include powders, fine granules, granules, tablets, capsules, injections, nasal drops, suspensions, drops, ointments, syrups, sustained release formulations and the like. These can be produced by a conventional method using a usual pharmaceutically acceptable carrier for the preparation, as in the case of the usual medicine.

[0149]

According to the present invention, there is provided an immunological function-suppressing agent containing the compound represented by the above general formula (I) as an active ingredient, and more specifically, is caused by abnormally enhanced immune function. Diseases, for example, treatment of so-called autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis, autoimmune hemolytic anemia and the like, and treatment for suppressing rejection at the time of organ transplantation; It is effective for treating inflammatory diseases and the like, particularly for treating autoimmune diseases such as rheumatoid arthritis.

[0150]

[Brief description of the drawings]

FIG. 1 is a graph showing the effect of the compound of the general formula (I) on suppressing the development of collagen arthritis.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 37/06 37/06 C07H 3/10 C07H 3/10 7/02 7/02 11/00 11 / 00 13/04 13/04 13/06 13/06 13/08 13/08 13/10 13/10 15/04 15/04 AG 15/18 15/18 17/04 17/04 // C07D 309 / 30 C07D 309/30 Z 407/12 407/12 493/08 493/08 B C07F 7/18 C07F 7/18 A (58) Field surveyed (Int. Cl. ⁷ , DB name) C07H 3/00- 23/00 A61K 31/70-31/714 CA (STN) CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (I) (Wherein R ¹ is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group, an alkynyl group, a —OSO ₂ R ⁷ group, a halogen atom, a —OCOR ⁷ group, a —NHCOR ⁸ group, an alkoxy group, or even a phenyl group embedded image In a represented by sugar derivative residue, R ² is a hydrogen atom or an alkyl group, R ³ is a hydrogen atom or a halogen atom, R ⁴ is a hydrogen atom, -COR ⁹ group, optionally substituted silyl a group or substituted alkyl group which may be, R ⁵ and R ^6, one hydroxyl group, an optionally substituted alkoxy group, the sugar derivative residue, a substituted or unsubstituted cycloalkyl group, or -OCOR a ¹⁰ group, and the other is an alkyl group which may be hydrogen atom or a substituent, R ⁴
And R ⁵ may together form a single bond, in which case R ⁶ is a hydrogen atom or an optionally substituted alkyl group, and R ⁷ , R ⁹ and R ¹⁰ are each an alkyl group or a substituted R ⁸ is an alkyl group, an optionally substituted phenyl group or a benzyloxy group, and X is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, Optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted furanyl group, optionally substituted thienyl group, formyl group , -COR ¹¹ group, -C (W ¹⁾ is W ² R ¹¹ group or -SO ₂ R ¹¹ group, R ¹¹ is an optionally substituted chain hydrocarbon group, which may be substituted monocyclic and carbonized Hydrogen group, polycyclic ring which may be substituted Hydrocarbon group, is being or a monocyclic heterocyclic group substituted substituted is also be polycyclic heterocyclic group, W ¹ is an oxygen atom or a sulfur atom, W ² represents an oxygen atom, a sulfur atom or -NH- group, and Y is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted or an alkynyl group which may be substituted), or a salt thereof. An immune function inhibitor characterized by containing as an ingredient. 2. An anti-inflammatory agent comprising the enopyranose derivative represented by the general formula (I) or a salt thereof as an active ingredient. 3. A compound of the formula (I-1) or (I-2) (Wherein R ¹ is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group, an alkynyl group, a —OSO ₂ R ⁷ group, a halogen atom, a —OCOR ⁷ group, a —NHCOR ⁸ group, an alkoxy group, or even a phenyl group embedded image In a represented by sugar derivative residue, R ² is a hydrogen atom or an alkyl group, R ³ is a hydrogen atom or a halogen atom, R ⁴ and R ⁵ form a single bond together, R ⁶ is a hydrogen atom or an optionally substituted alkyl group, R ⁷
Is an alkyl group or a phenyl group which may be substituted,
R ⁸ is an alkyl group, an optionally substituted phenyl group or a benzyloxy group; X represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, Optionally substituted cycloalkyl group, optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted furanyl group, optionally substituted thienyl group, formyl group, -COR ¹¹ group, -C
(W ¹ ) a W ² R ¹¹ group or a —SO ₂ R ¹¹ group, wherein R ¹¹ is an optionally substituted chain hydrocarbon group, an optionally substituted monocyclic hydrocarbon group, or an optionally substituted A polycyclic hydrocarbon group, an optionally substituted monocyclic heterocyclic group or an optionally substituted polycyclic heterocyclic group, W ¹ is an oxygen atom or a sulfur atom, W ² is an oxygen atom, A sulfur atom or a -NH- group,
Y is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, except for the following cases. In the formula (I-1), when R ¹ , R ² , R ³ , R ⁶ and X are a hydrogen atom and Y is a hydrogen atom or an alkyl group which may be substituted, ^{When 1} , R ² , R ³ , R ⁶ and Y are a hydrogen atom and X is acetyl, 3,5-dinitrobenzoyl or p-toluenesulfonyl, in (I-1), R ¹ , R ² , R ³ and Y are hydrogen atoms, R ⁶ is an alkyl group which may be substituted,
When X is a hydrogen atom or acetyl, in (I-2), when R ¹ , R ² , R ³ , R ⁶ and X are a hydrogen atom and Y is methyl, in (I-2), R ¹ , R ² , R ³ , R ⁶ and Y are hydrogen atoms, and X is a hydrogen atom, methyl, benzyl, formyl, acetyl, benzoyl, 4-chlorobenzoyl,
3,5-dichlorobenzoyl, 4-nitrobenzoyl,
In the case where it is 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl, and in (I-2), R ¹ is p-toluenesulfonyloxy; ² , R ³ , R ⁶ and Y are hydrogen atoms and X is a hydrogen atom, acetyl or p-toluenesulfonyl. ).