JP2528332B2 - Novel pseudo sugar derivative - Google Patents

Description

The present invention relates to a compound of the general formula [In the formula, Q ¹ and Q ² each represent a lower alkyl group, or both represent a lower alkylene group. R ¹ is a hydroxyl protecting group,
= X is = O, = NY (where Y is an optionally protected hydroxyl group), or (However, A is a hydrogen atom or an amine residue). ] The present invention relates to a novel pseudosugar derivative represented by the general formula [In the formula, R ³ represents a hydrogen atom or a hydroxyl-protecting group, and A represents an amine residue or a hydrogen atom. ] The method for producing variolamine or its derivative represented by

Pseudoamino sugars such as valienamine, validamine, variolamine and their N-substituted derivatives, especially
N-substituted derivatives of variolamine show strong α-glucosidase inhibitory activity [J. Med. Chem., Vol. 29, 1038-1046.
Page (1986)], a compound useful as a prophylactic or therapeutic agent for hyperglycemic symptoms in humans and animals and various diseases caused by it, such as diabetes, obesity and hyperlipidemia. The pseudosugar derivative [I] is an important compound as a raw material for producing variolamine and its N-substituted derivative.

2. Description of the Related Art Methods for producing valiolamine include a method of isolating from a culture solution of Streptomyces hygroscopicus subsp. Limoneus (Japanese Patent Laid-Open No. 57-169446) and a method of degrading validamycin. And a method of synthesizing valienamine or validamin obtained as a starting material (Japanese Patent Laid-Open No. 57-179174, 58-46044). In addition, DL-1,2,3-tri-O-acetyl- (1,3 / 2,4) -4
-Synthesis of DL-penta-N, O-acetylvaliolamine via bromo-6-methylene-1,2,3-cyclohexanetriol [S. Ogawa et al., Chem. Lett., 1581
−1582 (1985)].

Problems to be Solved by the Invention Although the above-mentioned method for producing variolamine by the direct fermentation method is the simplest method, at present, it is still problematic as an industrial method in terms of yield. Although the method for producing allamine is an excellent method as an industrial method, the molecular weight of valienamine, which is a constituent component, is about 1 / about that of the starting material, validamycin.
It is only 2.7, and there is a drawback that the obtained valienamine is expensive. Further, in the production method by chemical synthesis of S. Ogawa et al., The step of resolving the stereoisomer (DL-form) is unsolved.
Accordingly, there has been a strong demand for the production of a variolamine production method which is industrially more advantageous than these known production methods.

Means for Solving the Problems Therefore, as a result of intensive studies to solve the above-mentioned problems, the present inventors have found that D-glucose or D-glucono-1,5-lactone which is easily available and inexpensive A compound of the general formula [wherein the hydroxyl groups at the 2,3,4 and 6-positions of D-glucono-1,5-lactone which can be easily produced from (D-gluconic acid δ-lactone) are protected by a protecting group I]
We succeeded in synthesizing variolamine and its N-substituted derivative via the compound represented by. Hereinafter, the method for producing the compound [I] and the method for producing the variolamine and the derivative [II] from the compound [I] will be specifically described, and the production process formulas are shown in FIGS. 1 and 2. In each formula of FIGS. 1 and 2, Q ¹ and Q ² each represent a lower alkyl group or both represent a lower alkylene group. R ¹ represents a hydroxyl-protecting group, R ³ represents a hydrogen atom or a hydroxyl-protecting group, Y represents an optionally protected hydroxyl group, and A represents an amine residue or a hydrogen atom.

That is, the compounds represented by the general formulas [I] and [II] are, for example, compounds represented by the general formula in the D-glucono-1,5-lactone derivative (1). It can be produced via the compound (2) obtained by reacting the carbanion represented by. Incidentally, as the carbanion represented by the above general formula, in the formula, Q ¹ , Q ²
Is, for example, a carbanion showing a lower alkyl group such as methyl, ethyl, propyl or isopropyl, specifically, a carbanion derived from bis (methylthio) methane or bis (ethylthio) methane,
And, Q ¹ and Q ² are, for example, a compound in which both are lower alkylene groups such as ethylene and trimethylene, specifically,
For example, carbanions derived from 1,3-dithiolane and 1,3-dithiane can be mentioned. Hereinafter, for ease of understanding, as a preferable representative example of the carbanion represented by the above general formula, a carbanion derived from bis (methyltao) methane and 1,3-dithiane is used as an example, Steps 1 to 4 (FIG. 1) for producing compound (5) from (1) and step 5 for producing compounds (7) and (9) from compound (5)
8 (FIG. 2) will be described. That is, the compound (5) is obtained by, for example, the following steps 1 to 4,
That is, step 1: (i) a carbanion obtained by treating bis (methylthio) ethane with a base such as n-butyllithium is reacted with D-glucono-1,5-lactone derivative (1) to give D-glucon. -2-Hept-Sulose- (2,6)
A compound in which the hydroxyl group at the 3,4,5,7-position of 1,1- (dimethyl dithioacetal) is protected by a protecting group, that is, 1-
A step of producing a C- [bis (methylthio) methyl] -D-gluconopyranose derivative (2), or (ii) 1,3
-Carboxion obtained by treating dithian with a base such as n-butyllithium is reacted with D-glucono-1,5-lactone derivative (1) to form D-gluco-2-heptoseulose- (2 , 6) .1,1- (Trimethylene dithioacetal) is a compound in which the 3,4,5,7-position hydroxyl group is protected by a protecting group, that is, 1-C- (1,3-dithian-2- Yl) -D-glucopyranose derivative (2), Steps 2 to 3: 1-C by oxidizing the 6-position hydroxyl group of the D-gluco-2-heptoseulose derivative (2) to an oxo group −
Production of [bis (methylthio) methyl] -D-xylo-5-hexoseurose derivative or 1-C- (1,3-dithian-2-yl) -D-xylo-5-hexoseurose derivative (4) Step, that is, the carbonyl group forming the hemiketal of compound (2) is reduced to a hydroxyl group to open the pyranose ring and 1-C-
[Bis (methylthio) methyl] -D-glutitol derivative or 1-C- (1,3-dithian-2-yl) -D-
Step 2 for producing a glutitol derivative (3), and step 3 for producing a dioxo derivative (4) by oxidizing the hydroxyl groups at the 1-position and the 5-position of the glutitol derivative (3), Step 4: Compound (4) with a base By processing (1
S )-(1 (OH), 2,4 / 1,3) -1-C- (hydroxymethyl) -5-oxo-6,6-bis (methylthio) -1,2,
3,4-Cyclohexanetetrol derivative or (1 S )
-(1 (OH), 2,4 / 1,3) -1-C- (hydroxymethyl) -5-oxo-6,6- (trimethylenedithio) -1,
A 2,3,4-cyclohexanetetrol derivative (5) can be synthesized by the following steps.

Variolamine and its derivatives are described, for example, in FIG.
As shown in, the compound (5) can be used as a starting material. That is, for example, variol amine and its O-substituted derivative (7) can be prepared by reacting compound (5) with the general formula Y-NH ₂ (wherein Y is a hydroxyl group which may be protected). Compound (5) represented by reacting a compound represented by hydroxyamine or O-substituted hydroxylamine such as O-methylhydroxylamine or O-benzylhydroxylamine.
Oxime derivative or O-alkyl oxime or O-
Step of producing O-substituted oxime derivative (6) such as aralkyl oxime derivative, Step 6: subjecting compound (6) to desulfurization reaction to eliminate bis (methylthio) group or trimethylenedithio group (step 6a), the step of reducing the hydroxyimino group of the oxime to an amino group (step 6b), and the step of removing the protective group if necessary (step (6c)).

In addition, the N-substituted derivative of variolamine (9) (a compound in which A is an amine residue in the general formula [II]) is prepared by reacting the compound represented by the general formula R ² —NH ₂ (wherein R ² represents an amine residue), and a primary amine represented by
The obtained Schiff base was subjected to reduction reaction to give compound (8)
Step 8: subjecting compound (8) to a desulfurization reaction to eliminate the bis (methylthio) group or trimethylenedithio group,
If necessary, it can be synthesized through a step of removing the protecting group.

In the step 1, that is, when the 1-C- [bis (methylthio) methyl] -D-glucopyranose derivative (2) is produced from the D-glucono-1,5-lactone derivative (1), the compound (1 Is reacted with bis (methylthio) methyllithium to give 1-C- (1,3-
The dithian-2-yl) -D-glucopyranose derivative (2) is produced by reacting the compound (1) with 2-lithio-1,3-dithiane.
In this reaction, bis (methylthio) methyllithium or 2-lithio-1,3-dithiane is usually 1 to 5 molar equivalents, preferably 2 to 2.5 molar with respect to the D-glucono-1,5-lactone derivative (1). Used in equivalent amounts. This reaction is also carried out in a suitable solvent such as tetrahydrofuran, 1,4
-In dioxane, ethyl ether, hexane or the like inert solvent for this reaction alone or in a mixed solvent, preferably in an atmosphere of an inert gas such as nitrogen or argon. The reaction temperature is generally −20 ° C. to 78 ° C., preferably −50 ° C. to −78 ° C. in the initial stage of the reaction and −20 ° C. to 4.0 ° C. in the latter stage of the reaction. The reaction time is 1 to
About 8 hours is appropriate.

In the reaction of reducing the carbonyl group forming the hemiketal of the compound (2) to a hydroxyl group in step 2, examples of preferable reducing reagents when reducing with a reducing reagent include metal hydrogen complex compounds, diborane and substitution. Examples include diborane. More specifically, sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium trimethoxyborohydride, potassium tri-sec-butylborohydride, potassium triborohydride. -Sec-butylboron lithium, tri-sec-butylborohydride sodium, trisiamylborohydride potassium hydride, trisiamylborohydride lithium borohydride metal such as, for example, sodium cyanoborohydride, hydrogenation Alkali metal cyanoborohydride such as cyanoborotetra-n-butylammonium, for example, lithium aluminum hydride, lithium trimethoxyaluminum hydride, tri (tert-butoxy) hydride
Potassium aluminum hydride such as lithium aluminum, for example, 2,3-dimethyl-2-butylborane, bis-3-methyl-2-butylborane, diisopinocanphenylborane, dicyclohexylborane, 9-borabicyclo [3.3.1] Nonan, N, B-Enantran
Examples thereof include alkylboranes such as e), for example, dimethylamineborane, alkylamineboranes such as tetramethylammonium borohydride, and the like.

Although the temperature of these reduction reactions varies depending on the type of reducing agent, it is usually -30 ° C to 40 ° C, and in some cases, especially at the initial stage of the reaction, the reaction is performed by cooling to about -78 ° C. In some cases, heating is performed up to about 80 ° C. The reaction time also varies depending on the type of reducing agent and the reaction temperature, but the purpose can usually be achieved by reacting for several minutes to 24 hours.

In the reaction of oxidizing the unprotected hydroxyl group of the alditol derivative (3) in Step 3 to produce the dioxo derivative (4), the reaction conditions for oxidizing the secondary hydroxyl group of the saccharide or polyhydric alcohol to a carbonyl group are as follows. Used. For example, dimethylsulfoxide and trifluoroacetic anhydride, dimethylsulfoxide and acetic anhydride, dimethylsulfoxide and phosphorus pentoxide, dimethylsulfoxide and sulfur trioxide-pyridine complex, dimethylsulfoxide such as dimethylsulfoxide and oxalyl chloride, and an activation reagent thereof, preferably A method of oxidation using dimethyl sulfoxide and trifluoroacetic anhydride is used. Alternatively, a method of oxidizing with a chromium trioxide-pyridine complex, pyridinium dichromate, nicotinium dichromate, ruthenium oxide (VIII) or the like may be used.

The reaction conditions vary depending on the type of oxidizing agent used, but as the reaction solvent, for example, dichloromethane, chloroform, benzene, toluene, dimethylformamide, dimethylsulfoxide, acetic anhydride, etc. may be used alone or in combination, and the reaction is usually , −10 ° C. to 40 ° C., and in some cases, especially at the initial stage of the reaction, cooling to about −78 ° C. is performed. The reaction time is about 1 hour to 24 hours.

1-C-bis (methylthio) methyl-in step 4
D-xylo-5-hexoseurose derivative or 1-
C- (1,3-dithian-2-yl) -D-xylo-5-
Examples of the base used in the reaction of treating the hexoseulose derivative (4) with a base to undergo an intramolecular ring closure reaction to produce a polyhydroxy-substituted cyclohexanone derivative, that is, an inoseose derivative (5) include sodium acetate and acetic acid. Alkali metal salts such as potassium, potassium carbonate, sodium carbonate and potassium hydrogen carbonate, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, alkali metal hydrides such as sodium hydride, potassium hydride and lithium hydride, Examples thereof include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, and alkyl alkali metal such as butyl lithium and propyl lithium. Further, among the intramolecular ring closure reaction of the compound (4) to the compound (5) using a base, as a preferable method, for example, 18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-crown- In the presence of a crown ether such as 6,15-crown-5, a method of using an alkali metal salt such as sodium acetate, potassium carbonate or sodium carbonate as a base can be mentioned [Reference: PAAristoff, Synthe-ticC].
ommunication, 13: 145-150 (1983)]. The reaction solvent varies depending on the type of base used, but for example, aromatic hydrocarbons such as benzene and toluene, and ethers such as tetrahydrofuran, ethylene glycol monoethyl ether and ethyl ether are advantageously used. The reaction temperature also depends on the type of base and reaction solvent used,
Usually, it is carried out at a temperature within the range of 10 ° C to the boiling point of the solvent, and in some cases, especially at the initial stage of the reaction, cooling to about -78 ° C. The reaction time varies depending on the reaction temperature, but is usually about 1 to 18 hours.

The oxime (6) obtained by reacting the compound (5) with hydroxylamine whose hydroxyl group may be protected is subjected to a desulfurization reaction such as a bis (methylthio) group or a trimethylenedithio group, and the hydroxyl group is protected. Subjected to the reduction reaction of the hydroxyimino group part to the amino group,
The reduction reaction of an oxime to an amine in the step of producing a variol amine by subjecting it to a elimination reaction of a protective group, if necessary, can be carried out, for example, by using a platinum catalyst such as platinum oxide, palladium black or palladium carbon in a suitable solvent. Palladium catalyst such as, nickel catalyst such as Raney nickel, by subjecting to catalytic reduction using a rhodium catalyst such as Rhodiul carbon, etc., also using an aluminum hydride derivative such as lithium aluminum hydride, more preferably,
It can be performed by reducing in an atmosphere of an inert gas such as nitrogen or argon.

The reduction reaction of the oximes to the amino compound may be performed in a state where the hydroxyl group of the cyclitol moiety is protected, or may be performed after removing the hydroxyl-protecting group.

In step 7, the primary amine of compound (5) (general formula
The condensation reaction of the compound represented by R ² —NH ₂ with R ² being an amino residue) and the reduction reaction of the resulting Schiff base are generally carried out in a solvent. Suitable solvents include, for example, water, alcohols such as methanol, ethanol, propanol, butanol, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N-
Glymes such as methylacetamide, methylcellosolve, dimethylcellosolve, diethylene glycol methyl ether, ethers such as dioxane, tetrahydrofuran, ethyl ether, etc., or mixed solvents thereof, or these solvents or mixed solvents and benzene, toluene, acetic acid A mixed solvent with a non-polar solvent such as ethyl can be used.

The reaction temperature in this Schiff base formation reaction is not particularly limited, but is usually room temperature to about 100 ° C. The reaction time varies depending on the reaction temperature, but usually, the reaction can be achieved for several minutes to 24 hours for the purpose.

For the reduction reaction of the formed Schiff base, various metal hydride complex reducing agents, for example, sodium borohydride, potassium borohydride, lithium borohydride, hydrogen such as sodium methoxyborohydride, etc. Alkali metal borohydride, for example, alkali metal cyanoborohydride such as sodium cyanoborohydride, for example, aluminum aluminum hydride such as lithium aluminum hydride,
For example, dialkaline amine borane such as dimethylamine borane is advantageously used. When sodium cyanoborohydride is used, the reaction is preferably performed under acidic conditions, for example, in the presence of hydrochloric acid, acetic acid, or the like.

The temperature of this reduction reaction varies depending on the type of Schiff base to be reduced and the reducing agent, but is usually 0 ° C to 40 ° C, and in some cases, especially at the initial stage of the reaction, 0 ° C to -20 ° C.
It is carried out under moderate cooling and, if necessary, heated up to about 100 ° C. The reaction time also varies depending on the reaction temperature and the type of the Schiff base or reducing agent to be reduced, but usually the reaction can be achieved for several minutes to 24 hours to achieve the purpose.

As a reduction reaction of the formed Schiff base, a means of catalytic reduction can also be used. That is, it is carried out by shaking or stirring Schiff base in a suitable solvent in the presence of a catalyst for catalyst reduction in a hydrogen stream. Examples of the catalytic reduction catalyst include platinum black, platinum dioxide, palladium black,
Palladium carbon, Raney nickel, etc. are used, and examples of the solvent usually used include water; methanol,
Alcohols such as ethanol; ethers such as dioxane and tetrahydrofuran, N, N-dimethylformamide, a mixed solvent thereof and the like are used. The reaction is usually carried out at 0 ° C. to 40 ° C. under normal pressure, but it may be carried out under pressure or may be heated.

In the desulfurization reaction of the sulfur compounds represented by the general formulas (6) and (8) in steps 6 and 8, usually, Raney nickel saturated with hydrogen is suspended in a solution of the sulfur compound,
It is carried out by reacting with shaking or stirring. Raney nickel is usually used in a large excess (10 times (W / W) or more) with respect to sulfur compounds. Examples of the reaction solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol, water, ethers such as methyl cellosolve, dioxane and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, and aromatics such as benzene and toluene. Hydrocarbons, esters such as ethyl acetate, amides such as N, N-dimethylformamide, and other solvents that do not adversely affect this reaction are used alone or as a mixed solvent, preferably methanol, ethanol and the like. The reaction temperature is selected within the range of 0 ° C to 150 ° C, and is usually carried out at room temperature or the boiling point of the reaction solvent under heating under reflux. The reaction time varies depending on the type of Raney nickel and the reaction temperature, but is usually in the range of 10 minutes to 24 hours.

Compounds (5), (6) and (8) are all novel pseudosugar derivatives having a bis (methylthio) group or a 1,3-dithian-2-spiro substituent, and are useful target compounds (7 ) And (9), that is, important as intermediates of compound [II].

General formula The compound represented by the formula (wherein R ¹ represents a hydroxyl-protecting group) is also important as an intermediate compound for synthesizing the compound [II], and is obtained by subjecting the compound (5) to a reductive desulfurization reaction. It can be manufactured. This reductive desulfurization reaction needs to be carried out under a reaction condition that does not involve a reduction reaction of the carbonyl group of the compound (5). Preferred examples of this reaction condition include dioxane, tetrahydrofuran,
A method of reacting with Raney nickel in a nonpolar solvent such as benzene, toluene or ethyl acetate can be mentioned.

In the general formula [I] and FIGS. 1 and 2, the lower alkyl group represented by Q ¹ and Q ² is a lower alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. ^The lower alkylene group formed by both ¹ and Q ² has 2 to 2 carbon atoms such as ethylene and trimethylene.
And 3 lower alkylene groups.

The hydroxyl-protecting group represented by the general formulas [I] and [II] and R ¹ and R ³ in FIGS. 1 and 2 is a protecting group used as a hydroxyl-protecting group in sugar chemistry, for example, an ether-type protecting group. , Acetal-type protecting groups, ketal-type protecting groups, orthoester-type protecting groups, and, in some cases, acyl-type protecting groups.

Examples of the ether type protecting group include halogen, a lower alkoxy group having 1 to 5 carbon atoms, a benzyloxy group, and a lower alkyl group having 1 to 5 carbon atoms which may be substituted with a phenyl group; Alkenyl group; tri-substituted silyl group in which lower alkyl group having 1 to 5 carbon atoms, phenyl group, benzyl group and the like are substituents; lower alkoxy group having 1 to 5 carbon atoms, benzyl group optionally substituted with nitro group A lower alkoxy group having 1 to 5 carbon atoms; a tetrahydropyranyl group which may be substituted with a halogen and the like are used.

Examples of the above halogen include fluorine, chlorine, bromine and iodine, and examples of the alkyl having 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl. Examples of the alkoxy group having 1 to 5 carbon atoms, such as neopentyl group, are methoxy, ethoxy, propoxy, butoxy, pentyloxy, vinyloxy, allyloxy and the like, which may be substituted with halogen, having 2 to 2 carbon atoms.
Examples of the alkenyl group 4 include vinyl, allyl, isopropenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and the like.

More specific examples of the ether type protecting group include methyl, methoxymethyl, benzyloxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloromethoxymethyl, ethyl, 1-ethoxyethyl, 1 -Methyl-1-methoxyethyl, 2,2,2-trichloroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-betyl, ethoxyethyl, triphenylmethyl, p-methoxyphenyldiphenylmethyl; allyl; trimethylsilyl , tert-Butyldimethylsilyl, tert-butyldiphenylsilyl; benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl; tetrahydropyranyl, 3-bromotetrahydropyranyl, 4-methoxytetrahydropyranyl, tetrahydrofuranyl Etc.

As the acetal-type, ketal-type and orthoester-type protecting groups, those having 1 to 10 carbon atoms are advantageously used.
Specific examples include methylene, ethylidene, 1-tert-
Butylethylidene, 1-phenylethylidene, 2,2,2-trichloroethylidene; isopropylidene, butylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene; benzylidene, p-methoxybenzylidene, 2,4-
Dimethoxybenzylidene, p-dimethylaminobenzylidene, o-nitrobenzylidene; methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1,2-dimethoxyethylidene and the like.

Examples of the acyl-type protecting group include halogen, a lower alkoxy group having 1 to 5 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms which may be substituted with a phenoxy group which may have a halogen, a nitro group, A phenyl group, a benzoyl group optionally substituted by a lower alkyl group having 1 to 5 carbon atoms which may be substituted by halogen, and a benzoyl group optionally substituted by a lower alkyloxycarbonyl group having 2 to 6 carbon atoms Having 2 carbon atoms which may be substituted with halogen
~ 6 alkoxycarbonyl group, alkenyloxycarbonyl group having 3 to 5 carbon atoms, lower alkoxy group having 1 to 5 carbon atoms, or a benzyloxydicarbonyl group optionally substituted with a nitro group, substituted with a nitro group A phenoxycarbonyl group or the like is used.

As the halogen, the lower alkyl group having 1 to 5 carbon atoms, the lower alkoxy group having 1 to 5 carbon atoms and the alkenyl group having 2 to 4 carbon atoms, the same as those exemplified in the case of the ether-type protecting group are used. Can be

More specific examples of acyl-type protecting groups include formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, phenoxyacetyl, p-chlorophenoxyacetyl, propionyl,
Isopropionyl, 3-phenylpropionyl, isobutyryl, pivaloyl; benzoyl, p-nitrobenzoyl, p
-Phenylbenzoyl, o- (dibromomethyl) benzoyl, o- (methoxycarbonyl) benzoyl, 2,4,6-trimethylbenzoyl; methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isobutyloxycarbonyl; vinyl Oxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; p-nitrophenoxycarbonyl and the like.

In addition, a stannoxane type protecting group such as dibutylstannyl and tributylstannyl, a cyclic carbonate type protecting group, and a cyclic boronate type protecting group are also used depending on the kind of the compound.

The types of the protective groups for the hydroxyl groups represented by R ¹ and R ³ in the compound may be the same or may include two or more different protective groups. Further, for example, in the case of a cyclic acetal type, a cyclic ketal type, a cyclic orthoester type, a cyclic carbonate type, a cyclic boronate type, a stannoxane type protecting group, two hydroxyl groups may be protected by one protecting group.

Typical examples of the amine residue represented by R ² in the general formula R ² NH ₂ include a hydroxyl group which may be protected and / or a phenyl group which may be substituted, and may have 1 to 10 carbon atoms. 7 chain or cyclic hydrocarbons.

Specific examples of the primary amine represented by the general formula R ² NH ₂ include, for example, ethanolamine, 3-amino-1-propanol, 2-amino-1-propanol, 2-amino-
1,3-propanediol, 1-amino-2-propanol,
2-amino-3-hydroxy-1-butanol, tris (hydroxymethyl) aminomethane, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, 2-amino -3-Methyl-1-butanol, 3-amino-1,2-propanediol, 4-amino-1,2-butanediol, 2-amino-1-butanol, 2
-Amino-1,4-butanediol, 2-amino-1,5-pentanediol, 5-amino-1-pentanol, 6-amino-1-hexanol, methylamine, ethylamine, propylamine, butylamine, benzylamine , Phenethylamine, aminodiphenylmethane, 2-amino-1-
Phenylethanol, 2-amino-2-phenylethanol, 2-amino-3-phenyl-1-propanol, 2-amino-3-hydroxy-3-phenyl-1-propanol, 2-amino-3- (4-hydroxy Phenyl) -1-
Linear alkylamines that may have a hydroxyl group and / or an optionally substituted phenyl group, such as propanol and β-amino-α-methylphenethyl alcohol, for example, 1-amino-1-deoxy-D -Glutitol, 2-amino-2-deoxy-D-glutitol, 1-
Amino-1-deoxy-D-mannitol, 2-amino-
2-deoxy-D-galactitol, 1-amino-1-deoxy-D-ribitol, 4-amino-4-deoxy-D
-Amino-deoxy-alditols such as erythritol, eg trans-2-aminocyclohexane-1
-All, trans-3-aminocyclohexane-1-
All, cis-3-aminocyclohexan-1-ol, trans-2-amino-1-phenylcyclohexan-1-ol, cis-2-amino-1-phenylcyclohexan-1-ol, cyclohexylamine, cyclopentylamine, 1 -Amino-1-cyclopentanemethanol, 2-aminocyclopentanol and other cyclic alkylamines optionally substituted with a hydroxyl group and / or a phenyl group, for example, myo-inosamine-1, myo-inosamine-2, myo -Inosamine-4, Neo-Inosamine-2,
Inosamines such as epi-inosamine-2, muco-inosamine-3, scyllo-inosamine, for example, 2-aminomethyl-
C- (aminomethyl) inositols such as myo-inositol, for example, diaminocyclitols such as streptamine, deoxystreptamine, hotamine, sporamine, and histamine, for example, valienamine, validamine, hydroxyvalidamine, variolamine, 2-hydroxy. Pseudo amino sugars such as 4- (hydroxymethyl) cyclopentylamine and the like can be mentioned. Further, the hydroxyl group of the above compound may be protected. Specific examples of the amine residue represented by A include all the amine residues (that is, R ² ) of the amines listed as examples of the primary amine represented by R ² NH ₂ described above.

Specific examples of the “optionally protected hydroxyl group” represented by R ² and Y include, for example, lower alkoxy having 1 to 4 carbon atoms such as hydroxy, methoxy, ethoxy and trityloxy, and aralkyloxy group such as benzyloxy. Etc.

In the compound of the general formula [II], in which A is a hydrogen atom, that is, the compound (7), in the compound (8), the A portion is, for example, benzyl group, p-methoxybenzyl group, 3,4-
A compound that is a group generally used also as a protecting group for an amino group, such as a dimethoxybenzyl group or a di (p-methoxyphenyl) methyl group, is subjected to, for example, a hydrogenolysis reaction by catalytic reduction, a reaction with metallic sodium in liquid ammonia. ,
It can also be produced by subjecting it to a reaction generally used as an elimination reaction of a protecting group for an amino group, such as a reaction with an acid (for example, concentrated sulfuric acid-trifluoroacetic anhydride, acetic acid, trifluoroacetic acid, formic acid, etc.). it can.

When the compound [II] has a protected hydroxyl group, the elimination reaction of the protective group of the hydroxyl group can be carried out by a method known per se. For example, acetal-type protecting groups such as cyclohexylidene group, isopropylidene group and benzylidene group, and ether-type protecting groups such as trityl group and tetrahydropyranyl group which can be eliminated with acid are hydrochloric acid, acetic acid, trifluoroacetic acid, p -By hydrolyzing with an acid such as toluene sulfonic acid or a sulfonic acid type ion exchange resin, for example, an acyl type protecting group such as an acetyl group or a benzoyl group can be converted into ammonia, sodium hydroxide, barium hydroxide, sodium methoxide or the like Benzyl ether-type protecting groups such as benzyl group and p-methoxybenzyl group can be eliminated by hydrolysis with alkali or by hydrogenolysis by catalytic reduction or reductive decomposition with metallic sodium in liquid ammonia. it can.

The pseudo sugar derivative (5) shown in FIGS. 1 and 2,
Each compound including (6) and (8) can be prepared by any means known per se, for example, concentration, concentration under reduced pressure, filtration, centrifugation, drying,
Freeze-drying, adsorption, desorption, methods utilizing differences in solubility in various solvents (eg solvent extraction, phase transfer, precipitation, crystallization, recrystallization, etc.), chromatography (eg ion exchange resins, activated carbon, high-porous polymers) , Sephadex, Sephadex ion exchanger, cellulose, ion exchange cellulose, silica gel, chromatography using alumina, etc.) and the like.

Effect of the Invention Variolamine and N-substituted derivatives thereof, in particular N-substituted derivatives of valolamine, e.g.
[2-hydroxy-1- (hydroxymethyl) ethyl]
Since variolamine has a strong α-glucosidase inhibitory effect and suppresses the metabolism of carbohydrates, it has an inhibitory effect on blood glucose elevation, and has a hyperglycemic condition and various diseases caused by hyperglycemia, such as diabetes and obesity. It is a compound useful for the treatment and prevention of infectious diseases and hyperlipidemia.

The pseudosugar derivative [I] of the present invention is an important compound as a raw material for producing variolamine and N-substituted derivatives of variolamine as described below. These pseudosugar derivative [I] are D-glucose or D-Glucono-1,5-, which can be easily and inexpensively produced from D-glucose
Using a lactone as a raw material, a 1-C- [bis (methylthio) methyl] -D-glucopyranose derivative or 1-C-
It can be produced via (1,3-dithian-2-yl) -D-gluconopyranose derivative (2).

Compound [I] is a useful compound for the preparation of variolamine and N-substituted derivatives thereof, but especially N-
In the synthesis of a substituted variolamine derivative, when the raw material compound for constructing the N-substituent moiety is easily available as an amino compound, the compound [I] is used as an intermediate raw material to facilitate the purpose as compared with the use of biolamine. It is possible to synthesize things.

Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the scope of the present invention is not limited thereto. The mixing ratios of the mixed solvents used in Reference Examples and Examples were shown by volume ratio (v / v) unless otherwise specified. In addition, the NMR spectrum is Varian XL-100
A nuclear magnetic resonance apparatus (100MHz) or Bruker
r) Measured with an AC-300 nuclear magnetic resonance apparatus (300 MHz), tetramethylsilane (in deuterated chloroform) or 4,4-
Sodium dimethyl-4-silapentane-1-sulfonate (heavy water) was used as the internal standard.

Reference Example 1 2,3,4,6-tetra-O-benzyl-1-C- (1,3-dithian-2-yl) -D-glucopyranose [that is, 3,4,
5,7-Tetra-O-benzyl-D-gluco-2-hept-sulose (2,6) .1,1- (trimethylene dithioacetal)] 1,3-dithiane (2.4 g) was added to tetrahydrofuran (60 m
L), and n-hexane solution of n-butyllithium (1.6M, 12.5m
L) was added dropwise, and the mixture was stirred at -20 to -30 ° C for 2.5 hours. The reaction solution was cooled again to -70 to -75 ° C, and 2,3,4,6-tetra-O-
A solution of benzyl-D-glucono-1,5-lactone (5.4 g) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr. 10% (w / v) ammonium chloride solution (100 mL) was added to the reaction solution, and the resulting oily matter was washed with ethyl acetate (300 m
L). The ethyl acetate extract was washed with 2N hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel (250 mL) column chromatography, washed with toluene, and then toluene-
Elution with ethyl acetate (15: 1). The eluted fractions were concentrated to dryness under reduced pressure to give 2,3,4,6-tetra-O-benzyl-1-C- (1,3
-Dithian-2-yl) -D-glucopyranose (6.3
g) was obtained as a colorless syrup.

IR (CHCl ₃ ): 3452cm ^-1 ; C = 0 absorption (1700〜1800c
m ^-1 ) is not allowed.

[Α] ²⁶ _D + 4.4 ° (c = 1, CHCl ₃ ) ・ NMR (CDCl ₃ ) δ: 1.
82 to 2.06 (2H, m, -SCH ₂ C H _2- ), 2.22 to 2.36 (2H, m,-
SC H axCH ₂ −x2), 3.30 to 3.47 (2H, m, −SC H eqCH ₂ −x
2), 3.62 (1H, dd, J = 2.2Hz, 10.3Hz) and 3.68 (1H, d
d, J = 4.3Hz, 10.3Hz) (6-CH 2), 3.63 (1H, d, J = 1.6H
z, -SCHS-), 3.68 (1H, t ^* , J = 9.3Hz, 9.9Hz, 4-CH),
4.06 (1H, ddd, J = 2.2Hz, 4.3Hz, 9.9Hz, 5-CH), 4.11 (1
H, t, J = 9.2Hz, 3-CH), 4.31 (1H, dd, J = 1.6Hz, 9.2Hz, 2
--CH), 4.32 (1H, s, --OH); 4.48 (2H, s), 4.60 (1H, d, J
= 11.0Hz), 4.67 (1H, d, J = 11.3Hz), 4.88 (1H, d, J = 1)
1.0Hz), 4.92 (1H, d, J = 11.3Hz) and 4.94 (2H, s)
(PhC H ₂ −x4); 7.18 to 7.36 (20H, m, C ₆ H ₅ −x4) ( ^* apparent splitting pattern) Elemental analysis: C ₃₈ H ₄₂ O ₆ S ₂ calculated value (%): C, 69.27; H, 6.43; S, 9.73. Experimental value (%): C, 69.67; H, 6.43; S, 9.61. Reference example 2 2,3,4,6-tetra-O-benzyl-1-C- ( 1,3-dithian-2-yl) -D-glutitol 2,3,4,6-tetra-O-benzyl-1-C- (1,3-dithian-2-yl) -D-glucopyranose (9.76 g)
Tetrahydrofuran-ethyl ether (11: 4,150 mL)
Lithium aluminum hydride (2.44 g) was added little by little under ice water cooling, and the mixture was stirred at the same temperature for 3.5 hr. Methanol (10 mL) was added dropwise to the reaction solution, which was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and 2N hydrochloric acid (200 mL). The aqueous layer was further extracted with ethyl acetate (250 mL),
The ethyl acetate extracts were collected, washed with saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel (550 mL) column chromatography and eluted with toluene-ethyl acetate (9: 1), and then with toluene-ethyl acetate (5: 1) to give 2,3,4,6-tetra- O-benzyl-1-C- (1,3-dithian-2-
(1 R ). And (1 S ) of D-glutitol
The two stereoisomers of − were separated and eluted. The fraction eluted with toluene-ethyl acetate (9: 1) was concentrated under reduced pressure to dryness, and the isomer (5.44 g) showing [α] ²⁶ _D −9.5 ° (c = 1, CHCl ₃ ) was obtained as a colorless syrup. , Toluene-ethyl acetate (fractions eluted with 5: 1 were concentrated to dryness under reduced pressure to dryness of [α] ²⁶ _D
An isomer (1.1 g) showing −5.7 ° (c = 1, CHCl ₃ ) was obtained as a colorless syrup.

The previously eluted isomer: [α] ²⁶ _D −9.5 ° (c = 1, CHCl ₃ ) · NMR (CDCl ₃ ) δ: 1.
_{86~2.17 (2H, m, -SCH 2} C H 2 -), 2.67 (1H, ddd, J = 2.8
Hz, 10.0Hz, 13.3Hz) and 2.77 (1H, ddd, J = 2.8Hz, 10.1
Hz, 13.0Hz) (−SC H axCH ₂ −x2), 2.86 (1H, d, J = 5.2H
z, 5−OH), 2.93 to 3.05 (2H, m, −SC H eqCH ₂ −x2), 3.55
(1H, dd, J = 1.1Hz, 2.9Hz, 1-OH), 3.60 (1H, dd, J = 4.2H
z, 9.8Hz) and 3.64 (1H, dd, J = 6.9Hz, 9.8Hz) (6-C
H ₂ ), 3.93 (1H, dd, J = 3.2Hz, 6.1Hz, 4-CH), 3.99 (1H, t
^* , J = 3.2Hz, 4.1Hz, 3-CH), 4.01 to 4.03 (2H, m, 1-CH, 5
-CH), 4.16 to 4.22 (2H, m, 2-CH, -SCHS-); 4.51 (1H,
d, J = 11.8Hz), 4.55 (1H, d, J = 11.8Hz), 4.58 (1H, d, J
= 11.2Hz), 4.58 (2H, s), 4.61 (2H, s) and 4.67 (1
H, d, J = 11.2Hz) (PhC H 2 -x4); 7.26~7.38 (20H, m, C
₆ H ₅ −x4) ( ^* apparent division pattern). Elemental analysis: C ₃₈ H ₄₄ O ₆ S ₂ Calculated value (%): C, 69.06; H, 6.71; S, 9.70. Experimental value (%): C, 69.56; H, 6.85; S, 9.39. Isomer: [α] ²⁶ _D −5.7 ° (c = 1, CDCl ₃ ). _{NMR (CDCl 3) δ: 1.82~2.05} (2H, m, -SCH 2 C H 2 -), 2.
41~2.61 (2H, m, -SC H xCH 2 -x2), 2.66~2.83 (2H, m,
−SC H eqCH ₂ −x2), 2.86 (1H, d, J = 6.0Hz, 1−OH), 2.95
(1H, d, J = 5.2Hz, 5-OH), 3.63 (1H, dd, J = 5.1Hz, 11.3H
z) and 3.67 (1H, dd, J = 3.9Hz, 11.3Hz) (6-CH ₂ ),
3.76 (1H, dd, J = 3.1Hz, 7.2Hz, 4-CH), 3.78 (1H, d, J =
8.9Hz, -SCHS-), 4.00 (1H, ddd, J = 1.5Hz, 6.0Hz, 8.9H
z, 1-CH), 4.08 to 4.16 (1H, m, 5-CH), 4.18 (1H, dd, J =
3.1Hz, 8.3Hz, 3-CH), 4.38 (1H, dd, J = 1.5Hz, 8.3Hz, 2-
CH); 4.51 (1H, d, J = 11.9Hz), 4.56 (1H, d, J = 11.9H)
z), 4.58 (1H, d, J = 11.1Hz), 4.63 (1H, d, J = 11.1Hz),
4.67 (1H, d, J = 11.3Hz), 4.70 (1H, d, J = 11.3Hz), 4.82
(1H, d, J = 11.3Hz) and 4.91 (1H, d, J = 11.3Hz) (Ph
_{C H 2 -x4); 7.25~7.35 (} 20H, m, C 6 H 5 -x4). Elemental analysis (%): C ₃₈ H ₄₄ O ₆ S ₂ Calculated value (%): C, 69.06; H, 6.71; S, 9.70. Experimental value (%): C, 69.29; H, 6.86; S, 9.20. Reference Example 3 2,3,4,6-tetra-O- (tetrahydropyranyl) -1
-C- (1,3-dithian-2-yl) -D-glucopyranose [ie 3,4,5,7-tetra-O- (tetrahydropyranyl) -D-gluco-2-heptoseurose −
(2,6) · 1,1- (trimethylene dithioacetal)] n-hexane solution of n-butyllithium (1.6M solution,
2.5 mL) was added dropwise to a solution of 1,3-dithiane (4.8 g) in tetrahydrofuran (100 mL) in an argon stream at −65 to −70 ° C. with cooling, and then stirred at −20 to −30 ° C. for 2.5 hours. The reaction solution was cooled again to -70 to -75 ° C, and 2,3,4,6-tetra-O-
A solution of (tetrahydropyranyl) -D-glucono-1,5-lactone (10.3 g) in tetrahydrofuran (40 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was ice-cooled 10
% (W / v) ammonium chloride solution (300 mL) and the resulting oil was extracted twice with ethyl acetate (300 mL). The ethyl acetate extract was washed with water, 2N hydrochloric acid, and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel (500 mL) column chromatography, and the column was washed with toluene-ethyl acetate (9: 1) and then eluted with toluene-ethyl acetate (4: 1). The eluate fraction was concentrated to dryness under reduced pressure to give 2,3,4,6-tetra-O- (tetrahydropyranyl) -1-C- (1,3-dithiane-2).
-Yl) -D-glucopyranose white powder (10.7g)
I got

IR (KBr): 3448 cm ^-1 ; Absorption at C = 0 (1700 to 1800 cm ^-1 ) is not observed.

Elemental _{analysis: C 30 H 50 O 10 S} 2 Calculated (%):. C, 56.76 ; H, 7.94; S, 10.10 Found (%):. C, 57.17 ; H, 7.90; S, 9.83 Example 4 2,3,4,6-Tetra-O- (tetrahydropyranyl) -1
-C- (1,3-dithian-2-yl) -D-glutitol Lithium aluminum hydride (1.74 g) was added to 2,3,4,6-tetra-O- (tetrahydropyranyl) -1-C- ( 1,3
-Dithian-2-yl) -D-glucopyranose (6.9
g) of tetrahydrofuran-ethyl ether (3: 1,100 m
The solution L) was added little by little under cooling with ice water, and then stirred at the same temperature for 5 hours. Methanol was added to the reaction solution to terminate the reaction, and the mixture was concentrated under reduced pressure. Ethyl acetate (10
(0 mL) and 2N hydrochloric acid (80 mL) were added, and the insoluble material was filtered off,
The organic solvent layer was separated. The organic solvent layer was washed with water and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (400 mL), the column was washed with toluene (500 mL), and then eluted with toluene-ethyl acetate (3: 2), and then with toluene-ethyl acetate (1: 2). 2,3,4,6-
Tetra-O- (tetrahydropyranyl) -1-C- (1,
3- (dithian-2-yl) -D-glucitol (1
Two putative stereoisomers of R )-and ( 1S )-were separated and eluted. The fraction eluted with toluene-ethyl acetate (3: 2) was concentrated under reduced pressure to dryness, and a colorless syrup (3.45 g) was obtained. The fraction eluted with toluene-ethyl acetate (1: 2) was concentrated under reduced pressure to dryness. This gave a colorless syrup (1.52g).

. Toluene - ethyl acetate (3: 2) eluted isomer: Elemental _{analysis: C 30 H 52 O 10 S} 2 Calculated (%): C, 56.58; H, 8.23; S, 10.07 Found (%) :. C, 56.60; H, 8.25; S, 10.23 toluene - ethyl acetate (1: 2) eluted isomer: elemental _{analysis: C 30 H 52 O 10 S} 2 calculated (%): C, 56.58; H, 8.23; S, 10.07. Experimental value (%): C, 56.93; H, 8.02; S, 9.73. Reference example 5 2,3,4,6-tetra-O-benzyl-1-C- [bis ( Methylthio) methyl] -D-glucopyranose [ie, 3,
4,5,7-Tetra-O-benzyl-D-gluco-2-heptoseurose- (2,6) .1,1- (dimethyldithioacetal)] n-hexane solution of n-butyllithium ( 1.6M solution,
3.75 mL) in a solution of bis (methylthio) methane (6.13 mL) in tetrahydrofuran (150 mL) in an argon stream at -65-
After dropping to −75 ° C. under cooling, the mixture was stirred at −20 to −30 ° C. for 2.5 hours. The reaction solution was cooled again to -65 to -70 ° C, and 2,3,4,6-
Tetra-O-benzyl-D-glucono-1,5-lactone (16.2g) in tetrahydrofuran (60mL) solution was added dropwise, and the mixture was stirred at the same temperature for 1 hour and then ice-cooled 10% (w / v).
Added to ammonium chloride solution (300 mL). The resulting oily matter was extracted with ethyl acetate (300 mLx2), and the extract was extracted with water and 2N.
The extract was washed with hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl ether-petroleum ether (1: 4,500 mL) was added to the residue, and the mixture was left overnight in the refrigerator to prepare 2,3,4,6-tetra-O-benzyl-1.
White crystals (16.0 g) of -C- [bis (methylthio) methyl] -D-glucopyranose were obtained.

Melting point 96-97 ° C. [Α] ²⁵ _D −24.6 ° (c = 1, CHCl ₃ ). IR (KBr): 3394 cm ^-1 ; C = O absorption (1700 to 1800 cm ^-1 ) is not observed.

NMR (CDCl ₃ ) δ: 1.99 (3H, s), 2.14 (3H, s), 3.45 to 4.2
0 (7H, m), 4.39 (1H, s), 4.50 to 5.07 (8H, m), 7.05 to 7.
45 (20H, m). NMR (CDCl ₃ , 300MHz) δ: 1.97 (3H, s, CH ₃ S
−), 2.15 (3H, s, CH ₃ S−), 3.55 (1H, dd, J = 1.7Hz, 11.2
Hz) and 3.74 (1H, dd, J = 4.4Hz, 11.2Hz) (6-C
H ₂ ), 3.64 (1H, dd, J = 8.6Hz, 9.9Hz, 4-CH), 3.89 (1H,
s, (Mes) ₂ C H −), 3.98 (1H, ddd, J = 1.7Hz, 4.4Hz, 9.9H
z, 5-CH), 4.10 (1H, t ^* , J = 8.6Hz, 9.4Hz, 3-CH), 4.16
(1H, broad d, J = 9.4Hz, 2-CH), 4.44 (1H, broad
s, -OH); 4.49 (1H, d, J = 12.2Hz), 4.60 (1H, d, J = 12.2)
Hz), 4.64 (1H, d, J = 10.9Hz), 4.76 (1H, d, J = 11.5H)
z), 4.85 (1H, d, J = 10.9Hz), 4.92 (2H, s) and 5.00
(1H, d, J = 11.5Hz) (PhC H ₂ −x4); 7.24 to 7.34 (20H,
m, C ₆ H ₅ −x4) ( ^* apparent division pattern). Elemental analysis: C ₃₇ H ₄₂ O ₆ S ₂ Calculated value (%): C, 68.70; H, 6.54; S, 9.91. Experimental value (%): C, 68.61; H, 6.62; S, 9.64. Reference example 6 2,3,4,6-Tetra-O-benzyl-1-C- [bis (methylthio) methyl] -D-glutitol 2,3,4,6-tetra-O-benzyl-1-C- [bis ( Methylthio) methyl] -D-glucopyranose (14.0
g) was dissolved in tetrahydrofuran (140 mL), lithium aluminum hydride (2.8 g) was added little by little while cooling with ice water, and the mixture was stirred at the same temperature for 18 hours and further at room temperature for 3 hours. Methanol (50 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) and water (200 mL) were added to the residue under ice cooling, and the mixture was made acidic (pH 1) with 2N hydrochloric acid under stirring, then the ethyl acetate layer was separated, and the aqueous layer was washed with ethyl acetate (200 m
L). The ethyl acetate extracts were combined, washed with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel (50
Column chromatography (0 mL) and eluting with toluene-ethyl acetate (6: 1) to give 2,3,4,6-tetra-O-benzyl-
1-C-[bis (methylthio) methyl]-D-glucitol of (1 R) - and (1 S) - 2 one stereoisomer of was eluted separately. Fraction eluted earlier (550-900
mL) was concentrated to dryness under reduced pressure and [α] ²⁵ _D −5.8 ° (c = 1, CHCl 3
_The isomer (11.5 g) showing ₃ ) was used as a colorless syrup, and the later eluted fraction (1.1 to 1.8 L) was concentrated to dryness under reduced pressure to [α] ²⁵ _D −12.7 ° (c = 1, CHCl ₃ ). An isomer (0.9
g) was obtained as a colorless syrup.

Previously eluted isomer: NMR (CDCl ₃ ) δ: 2.12 (6H, s, CH ₃ S-x2), 2.84 (1H, d, J
= 5.2Hz, 5-OH), 3.44 (1H, dd, J = 0.5Hz, 2.6Hz, 1-O
H), 3.62 (2H, d , J = 4.8Hz, 6-CH 2), 3.85 (1H, dd, J = 0.
_{5Hz, 2.7Hz, (MeS) 2} (C H -), 3.93 (1H, dd, J = 3.5H
z, 6.2Hz, 4-CH), 4.03 (1H, t ^* , J = 3.5Hz, 4.2Hz, 3-C
H), 4.05 to 4.10 (1H, m, 5-CH), 4.15 (1H, dd, J = 4.2Hz,
8.3Hz, 2-CH), 4.23 (1H, td ^* , J = 2.6Hz, 2.7Hz, 8.3Hz, 1
-CH); 4.50 (1H, d, J = 11.9Hz), 4.55 (1H, d, J = 11.9H)
z), 4.58 (1H, d, J = 11.5Hz), 4.60 (1H, d, J = 11.2Hz),
4.61 (1H, d, J = 11.2Hz), 4.63 (1H, d, J = 11.5Hz), 4.65
(1H, d, J = 11.2Hz) and 4.71 (1H, d, J = 11.2Hz) (Ph
C H ₂ −x4); 7.24 to 7.38 (20H, m, C ₆ H ₅ −x4) ( ^* apparent division pattern). Elemental analysis: C ₃₇ H ₄₄ O ₆ S ₂ Calculated value (%): C, 68.49; H, 6.83; S, 9.88. Experimental value (%): C, 68.78; H, 6.92; S, 9.76. Isomer: NMR (CDCl ₃ ) δ: 1.97 (3H, s, CH ₃ S−), 1.99 (3H, s, CH ₃ S
−), 2.96 (1H, d, J = 5.2Hz, −OH), 3.05 (1H, d, J = 5.1H
z, -OH), 3.58~3.69 (3H , m, 1-CH, 6-CH 2), 3.73 (1H,
dd, J = 3.0Hz, 6.9Hz, 4-CH), 3.80 (1H, d, J = 9.1Hz, (Me
S) ₂ C H −), 4.08 to 4.15 (1H, m, 5-CH), 4.18 (1H, dd, J
= 3.0Hz, 8.3Hz, 3-CH), 4.37 (1H, dd, J = 1.5Hz, 8.3Hz, 2
-CH); 4.50 (1H, d, J = 11.9Hz), 4.55 (1H, d, J = 11.9H)
z), 4.57 (1H, d, J = 11.5Hz), 4.61 (1H, d, J = 11.5Hz),
4.68 (1H, d, J = 11.3Hz), 4.73 (1H, d, J = 11.4Hz), 4.82
(1H, d, J = 11.3Hz) and 4.94 (1H, d, J = 11.4Hz) (Ph
_{C H 2 -x4); 7.25~7.34 (} 20H, m, C 6 H 5 -x4). Elemental _{analysis: C 37 H 44 O 6 S} 2 Calculated (%):. C, 68.49 ; H, 6.83; S, 9.88 Found (%):. C, 68.82 ; H, 6.99; S, 9.58 Example 7 2,3,4,6-Tetra-O-benzyl-1-C- [bis (methylthio) methyl-D-xylo-5-hexoseurose trifluoroacetic anhydride (3.2 mL) in dichloromethane (2
0 mL) solution was added dropwise to a solution of dimethyl sulfoxide (2.2 mL) in dichloromethane (25 mL) under cooling at -65 to -70 ° C, and the mixture was stirred at the same temperature for 20 minutes, and then 2,3,4,6-tetra-O. - benzylidene -1-C-[bis (methylthio) methyl]-D-glucitol of (1 R) - and (1 S) - mixture of isomers in dichloromethane (20 mL) solution of (3.2 g) was added dropwise, the temperature It was stirred for 1 hour. Add triethylamine (5.
A solution of 8 mL) in dichloromethane (20 mL) was added dropwise at the same temperature with cooling, the mixture was stirred for 15 minutes, the cooling bath was removed, and the reaction temperature was 0.
Stir until the temperature rises to ° C. The reaction solution was added to a mixed solution of dichloromethane (100 mL) and ice water (50 mL), the dichloromethane layer was separated, washed with 2N hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel (250 mL) column chromatography, and the column was washed with toluene and then eluted with toluene-ethyl acetate (9: 1). The elution fraction was concentrated under reduced pressure to dryness, 2.
3,4,6-Tetra-O-benzyl-1-C- [bis (methylthio) methyl] -D-xylo-5-hexoseulose (2.9 g) was obtained as a colorless syrup.

[Α] ²⁵ _D −33.9 ° (c = 1, CHCl ₃ ). IR (CHCl ₃ ): 1731 cm ^-1 .Elemental analysis: C ₃₇ H ₄₀ O ₆ S ₂ Calculated value (%): C, 68.92; H, 6.25; S, 9.95. Experimental value (%): C, 69.22; H , 6.23; S, 9.74. Reference Example 8 2,3,4,6-Tetra-O-benzyl-1-C- [bis (methylthio) methyl] -D-xylo-5-hexoseulose dimethyl sulfoxide (12.2 mL Was added dropwise to a solution of trifluoroacetic anhydride (16 mL) in cyclochloromethane (57 mL) at −65 to −70 ° C. under cooling, and the mixture was stirred at the same temperature for 20 minutes. 2,3,4,6-
Tetra-O-benzyl-1-C- [bis (methylthio)
Methyl]-D-glucitol _([α] D -5.8 ° stereoisomers) in dichloromethane (100 mL) solution of (18.4 g) -
The mixture was added dropwise to 65 to -70 ° C under cooling, and the mixture was stirred at the same temperature for 1 hour. Furthermore, a dichloromethane (100 mL) solution of triethylamine (31.8 mL) was added dropwise to this reaction solution at −65 to −70 ° C. under cooling, the mixture was stirred at the same temperature for 15 minutes, the cooling bath was removed, and the reaction temperature was adjusted to 0 ° C. Stir until rising. The reaction mixture was added to a mixture of dichloromethane (240 mL) and ice water (240 mL) for partitioning, the dichloromethane layer was separated, washed with 2N hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. Then, 2,3,4,6-tetra-O-benzyl-1-C- [bis (methylthio) methyl] -D-xylo-5-hexoseulose (17.8 g) was obtained as a pale yellow syrup.

_{. IR (CHCl 3): 1729,1715cm} -1 NMR (CDCl 3) δ: 1.98 (3H, s, CH 3 S -), 1.99 (3H, s, CH 3 S
−), 4.01 and 4.12 (each 1H, ABq, J = 18.0Hz, 6−CH ₂ ),
4.13 (1H, dd, J = 3.7Hz, 4.9Hz, 3-CH), 4.19 (1H, d, J = 3
7Hz, 4-CH); 4.27 (1H, d, J = 12.2Hz), 4.31 (1H, d, J = 1)
2.2Hz), 4.38 (1H, d, J = 11.6Hz), 4.43 (1H, d, J = 11.0H
z), 4.49 (1H, d, J = 11.2Hz), 4.55 (1H, d, J = 11.6Hz),
4.62 (1H, d, J = 11.0Hz) and 4.74 (1H, d, J = 11.2H)
(PhC H ₂ −x4); 4.72 (1H, d, J = 4.9Hz, 2-CH), 4.97
(1H, s, (MeS) ₂ C H −), 7.15 to 7.37 (20H, m, C ₆ H ₅ −x
Four). Example 1 (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri-O-
Benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol Dimethyl sulfoxide (11.4 mL) in dichloromethane (165 mL) solution A solution of trifluoroacetic anhydride (16.3 mL) in dichloromethane (65 mL) was added dropwise to the mixture at -65 to -70 ° C with cooling, and the mixture was stirred at the same temperature for 30 minutes. 2,3,4,6-
Tetra-O-benzyl-1-C- (1,3-dithian-2
-Yl) -D-glutitol was added to a solution of an isomer (12.8 g) showing [α] _D -9.5 ° in dichloromethane (85 mL) at -65.
The mixture was added dropwise at -70 ° C and stirred at the same temperature for 1 hour. A solution of triethylamine (21.5 mL) in dichloromethane (125 mL) was added dropwise to the reaction solution at -65 ° C or lower, the mixture was stirred for 15 minutes, the cooling bath was removed, and the mixture was stirred until the reaction temperature rose to 0 ° C. The reaction solution was added to a mixed solution of dichloromethane (350 mL) and ice water (350 mL) for partitioning, and the dichloromethane layer was separated. The dichloromethane layer was washed with 2N hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to dryness.
The crude material of 2,3,4,6-tetra-O-benzyl-1-C- (1,3-dithian-2-yl) -D-xylo-5-hexoseulose (12.4 g) was converted into a light yellow color. Obtained as a syrup.
This syrup was subjected to column chromatography on silica gel (550 mL) and eluted with toluene-ethyl acetate (9: 1). The eluted fractions were concentrated under reduced pressure, ethyl ether-petroleum ether (1: 4,350 mL) was added to the residue, and the mixture was left overnight in the refrigerator (1 S ) -1 (OH), 2,4 / 1,3). -2,3,4-tri-O-benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol (7.1 g) was obtained as white crystals.

Melting point 139-141 ° C. [Α] ²⁶ _D −57.3 ° (c = 1, CHCl ₃ ). IR (KBr): 3432, 1728 cm ^-1 NMR (CDCl ₃ ) δ: 1.76 to 1.90 and 2.01 to 2.07 (each 1H, m,
−SCH ₂ C H ₂ −), 2.41 (1H, ddd, J = 2.3Hz, 12.3Hz, 14.2H
z, −SC H ax), 2.54 to 2.74 (2H, m, −SC H eqx2), 2.99 (1
H, s, -OH), 3.52 (1H, dt ^* , J = 3.5Hz, 13.5Hz, 13.9Hz,-
SC H ax), 3.85 and 4.03 (each 1H, ABq, J = 9.7Hz, −CH ₂ O
-), 4.05 (1H, t ^* , J = 9.3Hz, 9.7Hz, 3-CH), 4.41 (1H,
d, J = 9.3Hz, 2-CH); 4.56 (1H, d, J = 11.8Hz), 4.67 (1
H, d, J = 11.4Hz), 4.68 (1H, d, J = 11.8Hz), 4.73 (1H, d,
J = 10.7Hz), 4.74 (1H, d, J = 10.7Hz), 4.94 (1H, d, J = 1)
0.7Hz), 4.95 (1H, d, J = 10.7Hz) and 4.95 (1H, d, J =
_{11.4Hz) (PhC H 2 -x4)} ; 5.27 (1H, d, J = 9.7Hz, 4-C
H), 7.18~7.47 (20H, m , C 6 H 5 -x4) (* splitting patterns apparent). Elemental _{analysis: C 38 H 40 O 6 S} 2 Calculated (%):. C, 69.48 ; H, 6.14; S, 9.76 Found (%):. C, 69.69 ; H, 6.10; S, 9.74 Example 2 (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri-O-
Benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol Trifluoroacetic anhydride (3.2 mL) in dichloromethane (1
3 mL) solution was added dropwise to a solution of dimethyl sulfoxide (2.2 mL) in dichloromethane (35 mL) under cooling to -65 to -70 ° C,
The mixture was stirred at the same temperature for 30 minutes. The reaction solution was cooled to -65 to -70 ° C while 2,3,4,6-tetra-O-benzyl-1-C.
- (1,3-dithiane-2-yl)-D-glucitol _([alpha] isomer showing the D -5.7 °, 2.5 g) was added dropwise in dichloromethane (17 mL) was added. After stirring for 1 hour, triethylamine (4.2 A solution of (mL) in dichloromethane (25 mL) was added dropwise, and the mixture was stirred for 15 minutes. After removing the cooling bath and stirring until the reaction temperature rose to 0 ° C., the reaction solution was diluted with dichloromethane (65 m
L) and ice water (65 mL) were added for partitioning. The dichloromethane layer was separated, washed with 2N hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give 2,3,4,6-tetra-O-benzyl-1-C-. (1,3-Dithian-2-yl) -D-xylo-5-hexoseulose was obtained as a pale yellow syrup. This syrup (2.
5g) is dissolved in toluene (100mL), sodium acetate (2.5g) and 18-crown-6 (0.1g) are added, and 18
Stirred for hours. The insoluble matter was filtered off, washed with toluene (50 mL), the filtrate and the washing solution were combined, washed with 2N hydrochloric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol (20 mL) was added to the residue and left in the refrigerator overnight (1 S )-(1 (OH), 2,4 / 1,3).
White of -2,3,4-tri-O-benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol Crystals (2.0 g) were obtained.

Elemental analysis: C ₃₈ H ₄₀ O ₆ S ₂ Calculated value (%): C, 69.48; H, 6.14; S, 9.76. Experimental value (%): C, 69.42; H, 6.26; S, 9.81. Reference example 9 (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri-O-
Benzyl -1-C-(benzyloxymethyl) -5-oxo-1,2,3,4-cyclohexane tetrol (1 S) - (1 ( OH), 2,4 / 1,3) -2,3 , 4-Tri-O
Raney nickel (3.0 g) was added to a solution of -benzyl-5-oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol (1.1 g) in dioxane (30 mL) at 80 ° C. The mixture was stirred under heating for 1.5 hours. After filtering the insoluble matter and washing with dioxane, the filtrate and the washing liquid were collected and concentrated under reduced pressure. The residue was subjected to silica gel (100 mL) column chromatography, and eluted with toluene-ethyl acetate (6: 1). The eluted fractions were concentrated under reduced pressure, ethyl ether-petroleum ether (1: 1, 10 mL) was added to the residue, and the mixture was left overnight in the refrigerator (1 S )-(1 (OH), 2,4 / 1, 3) -2,3,4-tri-O-
White crystals of benzyl-1-C- (benzyloxymethyl) -5-oxo-1,2,3,4-cyclohexanetetrol were obtained.

84-85 ° C. [Α] ²² _D +45.1 ゜ (c = 1, CHCl ₃ ). IR (KBr): 3440,1735 cm ^-1 .NMR (CDCl ₃ ) δ: 2.39 (1H, d, J = 2.0Hz, -OH), 2.47 (1
H, d, J = 14.5Hz, 6-CHeq), 2.84 (1H, ddd, J = 0.9Hz, 2.0H
z, 14.5Hz, 6−CHax), 3.15 and 3.53 (1H, ABq, J = 8.6 each)
_{Hz, -CH 2 O -),} 4.01 (1H, t, J = 9.0Hz, 3-CH), 4.06 (1
H, d, J = 9.0Hz, 2-CH), 4.14 (1H, dd, J = 0.9Hz, 9.0Hz, 4
-CH); 4.41 (1H, d, J = 11.8Hz), 4.47 (1H, d, J = 11.8H)
z), 4.55 (1H, d, J = 10.7Hz), 4.56 (1H, d, J = 11.7Hz),
4.75 (1H, d, J = 10.7Hz), 4.95 (1H, d, J = 10.7Hz), 4.96
(1H, d, J = 11.7Hz) and 4.99 (1H, d, J = 10.7Hz) (Ph
_{C H 2 -x4); 7.15~7.42 (} 20H, m, C 6 H 5 -x4). Elemental analysis: C ₃₅ H ₃₆ O ₆ calculated value (%): C, 76.06; H, 6.57. Experimental value (%): C, 76.19; H, 6.59. Example 3 (1 S ) − (1 (OH)) , 2,4,5 / 1,3) -5-Amino-1-
C- (Hydroxymethyl) -1,2,3,4-cyclohexanetetrol (variolamine) (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri -O
-Benzyl-1-C- (benzyloxymethyl) -5-
Oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol (600 mg) in methanol (35 mL)
, Hydroxylamine hydrochloride (720 mg) and sodium acetate (1.4 g) were added, and the mixture was stirred at room temperature overnight and then heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic solvent layer was washed with 2N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and dried under reduced pressure. Residue (420mg) in methanol (10m
The L) solution was added to a mixture prepared by previously suspending Raney nickel (15 g) in methanol (50 mL) and stirring the mixture in a hydrogen stream at room temperature for 1 hour, and the mixture was heated under reflux for 2 hours. The reaction solution was filtered, the insoluble matter was washed with methanol and water, the filtrate and the washing solution were collected and concentrated under reduced pressure. Methanol (50m
L), Raney nickel (1.0 g) is added, and 3.5-4k
It was subjected to catalytic reduction overnight at room temperature under pressure to g / cm ² . The reaction solution was washed with methanol-water (1: 4), and the filtrate and the washing solution were collected and concentrated under reduced pressure. Amberlite CG-50 (NH ₄ ⁺
Type, 100 mL) column chromatography, after washing the column with water,
Elution was performed with 0.1N aqueous ammonia. The elution fraction was concentrated under reduced pressure,
The residue was subjected to column chromatography of Dowex 1x2 (OH ^- type, 30 mL) and eluted with water. The eluted fraction was concentrated under reduced pressure and freeze-dried to obtain white powder (35 mg) of variolamine.

[Α] ²⁵ _D + 19.6 ° (c = 1, H ₂ O). NMR (D ₂ O) δ: 1.68 (1H, dd, J = 3.8Hz, 15.5Hz, 6-CHa
x), 1.88 (1H, dd, J = 2.9Hz, 15.1Hz, 6-CHeq), 3.33 (1
H, q ^* , J = 2.9Hz, 3.8Hz, 4.2Hz, 5-CH), 3.41 (1H, d, J =
9.5Hz, 2-CH), 3.44 and 3.52 (each 1H, ABq, J = 11.3Hz,
−CH ₂ O−), 3.57 (1H, dd, J = 4.2Hz, 9.9Hz, 4-CH), 3.85
(1H, t ^* , J = 9.5Hz, 9.9Hz, 3-CH) ( ^* apparent division pattern). Elemental analysis: C ₇ H ₁₅ NO ₅ · H ₂ O Calculated value (%): C, 39.80; H, 8.11; N, 6.63. Experimental value (%): C, 39.89; H, 8.19; N, 6.48. Example 4 (1 S )-(1 (OH), 2,4,5 / 1,3) -5-[[2-hydroxy-1- (hydroxymethyl) ethyl] amino]-
1-C-(hydroxymethyl) -1,2,3,4-cyclohexane tetrol (1 S) - (1 ( OH), 2,4 / 1,3) -2,3,4- tri -O
-Benzyl-1-C- (benzyloxymethyl) -5-
Oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol (1.0 g) and 2-amino-1,3-propanediol (0.16 g) were combined with N, N-dimethylformamide ( 20 mL), the mixture was stirred at room temperature for 30 minutes, sodium cyanoborohydride (0.5 g) was added, and the mixture was stirred at 60 ° C. overnight. The reaction solution was concentrated under reduced pressure, toluene was further added, and N, N-dimethylformamide was distilled off azeotropically, and the residue was partitioned between ethyl acetate and water. 2% ethyl acetate layer (w /
v) The extract was washed with sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the residue (1.05g) in methanol (20mL) was previously prepared with Raney nickel (3g).
Was suspended in methanol (20 mL), and the mixture was stirred in a hydrogen stream for 30 minutes at room temperature, and the mixture was heated under reflux for 1 hour. The reaction solution was filtered, the insoluble matter was washed with methanol and water, the filtrate and the washing solution were collected, and concentrated under reduced pressure. The residue was dissolved in methanol-water (4: 1, 60 mL), Raney nickel (0.5 g) was added, and the mixture was subjected to catalytic reduction to 3.5-4 kg / cm ² under pressure at room temperature overnight. The catalyst was removed by filtration, washed with methanol and water, the filtrate and the washing liquid were collected and concentrated under reduced pressure. Amber light residue
It was subjected to column chromatography with CG-50 (NH ₄ ⁺ type, 180 mL) and eluted with water. The eluate was concentrated under reduced pressure, ethanol (5 mL) was added to the residue, and the mixture was heated under reflux for about 10 minutes and then left in the refrigerator overnight (1 S )-(1 (OH), 2,4,5 / 1. , 3) -5
[[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -1-C- (hydroxymethyl) -1,2,3,
White crystals of 4-cyclohexanetetrol (75 mg) were obtained.

Melting point 162-163 ° C. [Α] ²⁵ _D +26.2 ゜ (c = 1, H ₂ O). Elemental analysis: C ₁₀ H ₂₁ NO ₇ calculated value (%): C, 44.94; H, 7.92; N, 5.24. Experimental value (%): C, 44.81; H, 8.05; N, 5.08. Example 5 (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri-O-
(Tetrahydropyranyl) -1-C-[(tetrahydropyranyl) oxymethyl] -5-oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol and its (1 R ) - in dichloromethane (65 mL) solution of dichloromethane (65 mL) solution of dimethyl sulfoxide (4.42 ml) isomer trifluoroacetic anhydride (6.35mL), - (1 ( CH 2 OH), 2,4 / 1,3) The solution was added dropwise to -65 to -70 ° C under cooling and stirred at the same temperature for 30 minutes, and then 2,3,4,6-tetra-O-
A mixture of (1 R )-and (1 S ) -isomers of (tetrahydropyranyl) -1-C- (1,3-dithian-2-yl) -D-glutitol (5.18 g) in dichloromethane (40 mL). The solution was added dropwise and stirred at -65 to -70 ° C for 1 hour. A solution of triethylamine (8.4 mL) in dichloromethane (25 mL) was added dropwise to the reaction solution under cooling at the same temperature, and the mixture was stirred for 15 minutes, then, the cooling bath was removed and the mixture was stirred until the reaction temperature rose to 0 ° C. The reaction mixture was diluted with dichloromethane (100 mL) and ice water (150
mL), the dichloromethane layer was separated, washed with 2N hydrochloric acid, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 2,3,4,
6-Tetra-O- (tetrahydropyranyl) -1-C-
(1,3-Dithian-2-yl) -D-xylo-5-hexoseulose (5.0 g) was obtained as a colorless syrup. This ketose derivative (5.0 g) was dissolved in toluene (100 mL) and potassium carbonate (4.1 g) and 18-crown-6 (0.1 g) were added.
Was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was filtered, the insoluble matter was washed with toluene (100 mL), the filtrate and the washing solution were combined, ethyl acetate (100 mL) and water (100 mL) were added, and the mixture was stirred,
The organic solvent layer was separated. The organic solvent layer was washed with 2N hydrochloric acid, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel (40
(0 mL) was subjected to column chromatography and eluted with toluene-ethyl acetate (4: 1, 1.5 L), and subsequently with toluene-ethyl acetate (1: 1). The fraction (0.7 to 1.4 L) eluted with toluene-ethyl acetate (4: 1) was concentrated under reduced pressure to dryness to obtain a pale yellow powder (3.3 g). This powder was added to silica gel (250 m
L) column chromatography, wash the column with toluene (500 mL) and toluene-ethyl acetate (6: 1, 1.4 L),
Elution with toluene-ethyl acetate (2: 1). The elution fraction was concentrated under reduced pressure to dryness, and (1 S )-(1 (OH), 2,4 / 1,3) -2,
3,4-Tri-O- (tetrahydropyranyl) -1-C-
[(Tetrahydroxypyranyl) oxymethyl] -5-
A white powder (2.8 g) of oxo-6,6- (trimethylenedithio) -1,2,3,4-cyclohexanetetrol was obtained.

_{. IR (CHCl 3): 1726cm} -1 Elemental _{analysis: C 30 H 48 O 10 S} 2 Calculated (%):. C, 56.94 ; H, 7.65; S, 10.13 Found (%): C, 57.10; H , 7.84; S, 9.88. The fraction (1.9 to 2.3 L) eluted with toluene-ethyl acetate (1: 1) in the previous chromatography was concentrated to dryness under reduced pressure (1 R )-
A pale yellow powder (1.05 g) presumed to contain isomers was obtained.

_{IR (CHCl 3):. 1732cm} -1 Example 6 (1 S) - (1 (OH), 2,4 / 1,3) -2,3,4- tri -O-
Benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6-bis (methylthio) -1,2,3,4-cyclohexanetetrol 2,3,4,6 obtained in Reference Example 8 -Tetra-O-benzyl-1-C- [bis (methylthio) methyl] -D-xylo-5-hexoseulose (17.8 g) was added to silica gel (900
mL) column chromatography, the column was washed with toluene, and then eluted with toluene-ethyl acetate (9: 1). The elution fraction was concentrated under reduced pressure, and the residue was again subjected to silica gel (600 mL) column chromatography, and toluene-ethyl acetate (10: 1) was used.
Eluted at. The eluted fractions were concentrated under reduced pressure, ethyl ether-petroleum ether (1: 10,300 mL) was added to the residue, and the mixture was left overnight in the refrigerator (1 S )-(1 (OH), 2,4 / 1,3). ) −2,3,
4-tri-O-benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6-bis (methylthio) -1,2,
White crystals (11.2 g) of 3,4-cyclohexanetetrol were obtained.

Melting point 97-98 ° C. IR (KBr): 3324,1732 cm ⁻¹ . [Α] ²² _D −35.6 ° (c = 1, CHCl ₃ ). NMR (CDCl ₃ ) δ: 1.83 (2H, s, CH ₃ S−), 2.12 (3H, s, CH ₃ S
−), 2.86 (1H, s, −OH, 3.79 and 3.87 (each 1H, ABq, J =
_{9.3Hz, -CH 2 O -),} 4.08 (1H, t, J = 9.3Hz, 3-CH), 4.66
(1H, d, J = 9.3Hz, 2-CH); 4.43 (1H, d, J = 11.8Hz), 4.5
5 (1H, d, J = 11.8Hz), 4.65 (1H, d, J = 11.3Hz), 4.71 (1
H, d, J = 10.8Hz), 4.79 (1H, d, J = 10.8Hz), 4.92 (1H, d,
J = 11.3Hz) and 4.95 (2H, d, J = 10.8Hz) (PhC H ₂ −
x4); 5.05 (1H, d, J = 9.3Hz, 4-CH), 7.17 to 7.43 (20H,
m, C ₆ H ₅ −x4). Elemental analysis: C ₃₇ H ₄₀ O ₆ S ₂ Calculated value (%): C, 68.92; H, 6.25; S, 9.95. Experimental value (%): C, 69.11; H, 6.26; S, 10.07. Example 7 (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri-O-
Benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6-bis (methylthio) -1,2,3,4-cyclohexanetetrol 2,3,4,6 obtained in Reference Example 7 -Tetra-O-benzyl-1-C- [bis (methylthio) methyl] -D-xylo-5-hexoseulose (2.9 g) in toluene (100 m
L) solution with sodium acetate (2.9 g) and 18-crown-6
(0.1 g) was added, and the mixture was stirred at room temperature for 18 hours. The insoluble material was filtered off and washed with toluene (50 mL). The filtrate and the washing solution were combined, washed with 2N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl ether-petroleum ether (1: 5,60 mL) was added to the residue and left overnight in the refrigerator (1 S )-(1 (OH), 2,4 / 1,3)-
2,3,4-Tri-O-benzyl-1-C- (benzyloxymethyl) -5-oxo-6,6-bis (methylthio)-
White crystals of 1,2,3,4-cyclohexanetetrol (2.1
g) was obtained.

Elemental analysis: C ₃₇ H ₄₀ O ₆ S ₂ Calculated value (%): C, 68.92; H, 6.25; S, 9.95. Experimental value (%): C, 68.88; H, 6.19; S, 10.08. Reference example 10 (1 S )-(1 (OH), 2,4 / 1,3) -2,3,4-tri-O-
Benzyl -1-C-(benzyloxymethyl) -5-oxo-1,2,3,4-cyclohexane tetrol (1 S) - (1 ( OH), 2,4 / 1,3) -2,3 , 4-Tri-O
-Benzyl-1-C- (benzyloxymethyl) -5-
Raney nickel (3.0 g) was added to a solution of oxo-6,6-bis (methylthio) -1,2,3,4-cyclohexanetetrol (1.0 g) in dioxane (30 mL), and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was filtered off, washed with dioxane, the filtrate and the washing solution were combined, and concentrated under reduced pressure. Silica gel (150m
L) was subjected to column chromatography and eluted with toluene-ethyl acetate (6: 1). The eluted fractions were concentrated under reduced pressure, ethyl ether-petroleum ether (1: 8,10 mL) was added to the residue, and the mixture was left overnight in the refrigerator (1 S )-(1 (OH), 2,4 / 1, 3)
White crystals (360 mg) of -2,3,4-tri-O-benzyl-1-C- (benzyloxymethyl) -5-oxo-1,2,3,4-cyclohexanetetol were obtained.

84-85 ° C. [Α] ²² _D +45.1 ゜ (c = 1, CHCl ₃ ). IR (KBr): 3440,1735 cm ^-1 .NMR (CDCl ₃ ) δ: 2.39 (1H, d, J = 2.0Hz, -OH), 2.47 (1
H, 4, J = 14.5Hz, 6-CHeq), 2.84 (1H, ddd, J = 0.9Hz, 2.0H
z, 14.5Hz, 6−CHax), 3.15 and 3.53 (1H, ABq, J = 8.6 each)
_{Hz, -CH 2 O -),} 4.01 (1H, t, J = 9.0Hz, 3-CH), 4.06 (1
H, d, J = 9.0Hz, 2-CH), 4.14 (1H, dd, J = 0.9Hz, 9.0Hz, 4
-CH); 4.41 (1H, d, J = 11.8Hz), 4.47 (1H, d, J = 11.8H)
z), 4.55 (1H, d, J = 10.7Hz), 4.56 (1H, d, J = 11.7Hz),
4.75 (1H, d, J = 10.7Hz), 4.95 (1H, d, J = 10.7Hz), 4.96
(1H, d, J = 11.7Hz) and 4.99 (1H, d, J = 10.7Hz) (Ph
_{C H 2 -x4); 7.15~7.42 (} 20H, m, C 6 H 5 -x4). .. Elemental analysis: C ₃₅ H ₃₆ O ₆ Calculated (%): C, 76.06; H, 6.57 Found (%): C, 75.98; H, 6.71 Example 8 (1 S) - (1 (OH) , 2,4,5 / 1,3) -5-[[2-Hydroxy-1- (hydroxymethyl) ethyl] amino]-
1-C-(hydroxymethyl) -1,2,3,4-cyclohexane tetrol (1 S) - (1 ( OH), 2,4 / 1,3) -2,3,4- tri -O
-Benzyl-1-C- (benzyloxymethyl) -5-
Oxo-6,6-bis (methylthio) -1,2,3,4-cyclohexanetetrol (1.0 g) and 2-amino-1,3-propanediol (0.2 g) were dissolved in ethanol (20 mL), After stirring at room temperature for 4 hours, sodium cyanoborohydride (0.
5 g) was added and the mixture was stirred at 60 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% (w / v) sodium chloride solution. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained (1.0
g) ethanol (20 mL) solution, Raney nickel (3
g) was suspended in ethanol (30 mL), and the suspension was added to a mixture previously stirred in a hydrogen stream for 30 minutes at room temperature, and the mixture was heated under reflux for 30 minutes. The reaction solution was filtered, the insoluble matter was washed with methanol and water, the filtrate and the washing solution were collected, and concentrated under reduced pressure. The residue was dissolved in methanol-water (4: 1, 80 mL), Raney nickel (0.5 g) was added, and the mixture was subjected to catalytic reduction to 3.5-4 kg / cm ² under pressure at room temperature overnight. After removing the catalyst by filtration and washing with methanol and water, the filtrate and washings were collected and concentrated under reduced pressure. The residue was partitioned between water and ethyl ether, and the aqueous layer was concentrated under reduced pressure. The residue was subjected to Amberlite CG-50 (NH ₄ ⁺ type, 180 mL) column chromatography and eluted with water. The elution fraction was concentrated under reduced pressure,
Ethanol (5 mL) was added to the residue, and the mixture was heated under reflux for about 10 minutes, and then left in the refrigerator overnight (1 S )-(1 (OH), 2,
White crystals of 4,5 / 1,3) -5-[[2-hydroxy-1 (hydroxymethyl) ethyl] amino] -1-C- (hydroxymethyl) -1,2,3,4-cyclohexanetetrol (70 mg) was obtained.

Example 9 (1 S )-(1 (OH), 2,4,5 / 1,3) -5-amino-1-
C- (Hydroxymethyl) -1,2,3,4-cyclohexanetetrol (pariolamine) (1 S )-(1 (OH), 2,4,5 / 1,3) -2,3,4 -Tri-
O-benzyl-1-C- (benzyloxymethyl) -5
-Oxo-6,6-bis (methylthio) 1,2,3,4-cyclohexanetetrol (1.0 g) was dissolved in methanol (50 mL) and hydroxylamine hydrochloride (720 mg) and sodium acetate (1.4 g) were added. The mixture was stirred at room temperature for 15 days. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with 2N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution of the residue (1.1 g) in methanol (50 mL) was added to Raney nickel (5 g) which was previously suspended in methanol (50 mL) and stirred in a hydrogen stream for 1 hour, and the mixture was heated under reflux for 1 hour. The reaction solution was filtered, the insoluble matter was washed with methanol and water, the filtrate and the washing solution were collected and concentrated under reduced pressure. The residue was dissolved in methanol (50 mL), Raney nickel (1.0 g) was added, and the mixture was catalytically reduced to 3.5 to 4 kg / cm ^-2 at room temperature under pressure overnight. The reaction solution was filtered, the insoluble matter was washed with methanol and water, the filtrate and the washing solution were collected and concentrated under reduced pressure. The residue was subjected to Amberlite CG-50 (NH ₄ ⁺ type, 100 mL) column chromatography, and the column was washed with water and then eluted with 0.1N aqueous ammonia.
The eluted fraction was subjected to column chromatography with Dowex 1x2 (OH ^- type, 50 mL) and eluted with water. After the elution fraction was concentrated under reduced pressure,
Lyophilization yielded a white powder of variolamine.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07H 15/14 C07H 15/14 // A61K 31/12 A61K 31/12 31/13 31/13 31 / 21 ACN 31/21 ACN 31/70 ADP 31/70 ADP

Claims (1)

(57) [Claims] 1. A general formula [In the formula, Q ¹ and Q ² each represent a lower alkyl group, or both represent a lower alkylene group. R ¹ is a hydroxyl protecting group,
= X is = O, = NY (where Y is an optionally protected hydroxyl group), or (However, A is a hydrogen atom or an amine residue.) Is shown. ] The new pseudo sugar derivative represented by these.