JP3138834B2 - Method for producing fucopyranose analog and intermediate compound thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel process for producing fucopyranose analogs and a novel synthetic intermediate compound obtained by the process.

[0002]

2. Description of the Related Art Conventionally, synthesis of fucopyranose analogs such as 5-deoxy-5-thio-L-fucopyranose and 1,5-dideoxy-1,5-imino-L-fucitol useful as L-fucosidase inhibitors and the like. Methods are known (eg [J. Carbohydr. Chem.,
9, 683, (1990)], [J. Chem.
Soc. Chem. Commun. , 841-842
, (1985)], [J. Chem. Soc. , P
erkin. Trans. I, 665-667,
(1989)]).

[0003] However, the above-mentioned conventional synthesis method requires many steps, or has difficulty in obtaining raw materials or has a problem to be solved.

[0004]

The problem to be solved by the present invention is that a conventionally known method for synthesizing a fucopyranose analog requires a number of steps or it is difficult to obtain a raw material. is there.

[0005]

DISCLOSURE OF THE INVENTION The process for producing a fucopyranose analog according to the present invention comprises a D-arabinofuranoside derivative represented by the following general formula (I):

[0006]

Embedded image

The following general formula (II)

[0008]

Embedded image (Wherein R ₃ represents a lower alkyl group; the same applies hereinafter), and the 5-position hydroxyl group is converted to a leaving group by sulfonylation, and then reacted with a thiocarboxylate or an azide compound. Let me

The following general formula (III)

General formula

Embedded image (Wherein, X represents a lower acylthio group or an azido group; the same applies hereinafter). After acetic acid decomposition, the protective group is removed and the resulting hydroxyl group is acetylated to give the resulting acetyl. The compound represented by the following general formula (IV), wherein the compound is deacetylated or reduced after deacetylation:

General formula

Embedded image (Wherein, R ₄ represents a hydrogen atom or a hydroxyl group, and Y represents a sulfur atom (S) or an imino group (NH); the same applies hereinafter).

Here, in the description of the present specification, in the definition of the group of the general formula, "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Accordingly, the “lower alkyl group” includes, for example, methyl group, ethyl group, propyl, isopropyl group,
Butyl group, isobutyl group, etc., as "thio lower acyl group", for example, thioacetyl group, thiopropionyl group,
As the “trialkylsilyl group” such as a thiovaleryl group, for example, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group and the like are used.

Hereinafter, the manufacturing method of the present invention will be described.

The method for producing a fucopyranose analog of the present invention is shown by the following steps.

[0015]

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The D-arabinofuranoside derivative represented by the general formula (I) used as a starting material in the production method of the present invention is prepared by using an arabinofuranoside derivative represented by the following general formula (VI) as a raw material. It can be obtained by a production process shown in the following scheme via a compound represented by the general formula (VII).

[0017]

Embedded image

The above general formula (VI) and general formula (V
In II), R ₁ represents a trialkylsilyl group, R ₂ represents a lower alkyl group, and R ₅ represents an acyl group.

Here, the "acyl group" includes acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, hexanoyl, benzoyl and the like.

An example of a method for producing a raw material will be described in more detail. First, an arabinofuranoside derivative represented by the general formula (VI) is prepared under alkaline conditions using an alkoxide such as sodium methoxide, sodium ethoxide and potassium ethoxide. , In a solvent such as methanol, ethanol, dioxane, and tetrahydrofuran to remove the protecting group (acyl group) of the hydroxyl group at the 2,3,5-position,
Next, an acylating agent having a high selectivity for the 5-position hydroxyl group such as an acyl halide such as pivaloyl chloride or benzoyl chloride is prepared by using a suitable reaction solvent such as benzene, toluene, methylene chloride or chloroform which is inert to the reaction. By reacting, a protecting group (acyl group) is introduced into the 5-position hydroxyl group.

Next, a silylating agent corresponding to the trialkylsilyl group represented by the substituent R ₁ (for example, t-chloride)
Butyldimethylsilyl, t-butyldiphenylsilyl chloride, etc.) using an appropriate reaction solvent such as, for example, benzene, tetrahydrofuran, dimethylformamide, acetonitrile, dioxane, etc. to silylate the hydroxyl group at the 2,3-position. By reducing with lithium aluminum hydride, sodium borohydride or the like to remove the protecting group (acyl group) at the 5-position, the compound represented by the general formula (VII)
(Step A) in which the compound represented by is produced is not limited to this method, but may be another known production method.

Then, the compound represented by the general formula (VII) obtained in the above step A is oxidized to oxidize the D-arabinofuranoside represented by the general formula (I) which is a starting material of the production method of the present invention. A derivative is produced (Step B).

The oxidation of the compound represented by the general formula (VII) in the step B can be carried out using dimethyl sulfoxide or the like in the presence of oxalyl dichloride (so-called Swan oxidation).

The above-mentioned oxidation is carried out by reacting one equivalent of the compound represented by the general formula (VII) with 2 to 3 oxalyl dichlorides.
Equivalents and 4-6 equivalents of dimethyl sulfoxide,
By reacting at -70 ° C for 30 to 40 minutes, a D-arabinofuranoside derivative represented by the general formula (I) can be obtained.

The oxidation may be carried out using an oxidation method using pyridinium chlorochromate, or an oxidation method using dimethyl sulfoxide and dicyclohexylcarbodiimide.

The arabinofuranoside derivative represented by the general formula (VI) is obtained by methylating the 1-position hydroxyl group and benzoylating the 2,3- and 5-position hydroxyl groups using D-arabinose as a raw material. In (VI), R ₂
Is a methyl group, and R ₅ is a benzoyl group. Am. Chem. Soc. , 8
0, p. 2007, (1958)] and can be produced by known methods using known raw materials.

In the first step and the 1-1 step, a D-arabinofuranoside derivative represented by the general formula (I) as a starting material is reacted with a lower alkyl metal compound to form a lower alkyl represented by R3 at the 5-position. This is the step of introducing a group.

By selecting the type of the lower alkyl metal compound used here, the furanoside derivative represented by the general formula (II) can be preferentially produced (the first step), By selecting a lower alkyl metal compound, the furanoside derivative represented by the general formula (V) can be preferentially generated (Step 1-1). Furthermore, both compounds can be produced together, and can be separated by chromatography using silica gel or the like.

The lower alkyl metal compound suitable for preferentially producing the furanoside derivative represented by the general formula (II) (first step) includes alkyl lithium having an alkyl group represented by R ₃ and trialkyl. Examples thereof include aluminum, alkyldichlorocesium, and alkyltriisopropoxytitanium. In particular, trialkylaluminum is preferable, and when the furanoside derivative represented by the general formula (V) is preferentially formed (step 1-1). Suitable lower alkyl metal compounds include, for example, Grignard reagents such as alkylmagnesium bromide, alkylmagnesium iodide or lithium dialkyl cuprates.

The reaction is carried out by using 3 to 5 equivalents of the lower alkyl metal compound per equivalent of the D-arabinofuranoside derivative represented by the general formula (I) and a reaction solvent inert to the reaction (for example, ether, tetrahydrofuran, n-Hexane) under cooling.

In the second step, methanesulfonylation (mesylation), p-toluenesulfonylation (tosylation), and trifluorosulfonation are performed on the 5-position hydroxyl group of the furanoside derivative represented by the general formula (II) obtained in the first step. The compound is converted to a leaving group by sulfonylation such as methanesulfonylation and then reacted with a thiocarboxylate or an azide compound to obtain a compound represented by the above general formula (III). First, mesyl chloride, tosyl Chloride, sulfonic acid halides such as trifluoromethanesulfonyl chloride are reacted under a solvent such as pyridine and lutidine,
Further, the compound is reacted with a thiocarboxylate such as potassium thioacetic acid or an azide compound such as sodium azide to obtain a compound represented by the general formula (III).

In the third step, the furanoside derivative represented by the general formula (III) obtained in the second step is acetylated, and the obtained acetyl compound is hydrolyzed or reduced after hydrolysis to produce the present invention. This is a step of producing a fucopyranose analog represented by the general formula (IV), which is a final product in the method.

Acetylation is performed by a conventional method using a reactive derivative of acetic acid, for example, with acetic anhydride, acetyl chloride or the like in a solvent such as acetic acid (preferably hydrochloric acid,
In the presence of a strong acid such as sulfuric acid), ether-type protecting groups such as trialkylsilyl groups and alkyl groups are removed, and new protecting groups (acetyl groups) are introduced.
An acetyl compound represented by the formula is obtained. In the formula, Ac means an acetyl group.

General formula (VIII)

[0035]

Embedded image

In the case where X in the above formula (VIII) is a lower acylthio group, methanol, ethanol, dioxane, tetrahydrofuran and the like can be obtained under alkaline conditions with alkoxides such as sodium methoxide, sodium ethoxide and potassium ethoxide. Alkaline hydrolysis in a solvent of the formula (1), and when X is an azide group, similarly hydrolyzed, followed by catalytic reduction by a conventional method using a catalyst such as palladium-carbon, palladium black, Raney nickel, etc. ) Is obtained.

The above-mentioned general formula (I) obtained by the above manufacturing steps
V) The fucopyranose analog shown is isolated by a conventional method using, for example, extraction with an organic solvent, recrystallization, chromatography and the like.

[0038]

According to the present invention, 5-deoxy-5-thio-L which is conventionally useful as an L-fucosidase inhibitor or the like is known.
-Fucopyranose analogs such as fucopyranose and 1,5-dideoxy-1,5-imino-L-fucitol can be produced in a small number of steps and using easily available raw materials.

[0039]

Next, the present invention will be described in more detail with reference to examples. It should be noted that the present invention is not limited by these embodiments.

Example 1 This example shows an example of the production process of [5-deoxy-5-thio-L-fucopyranose], and is based on the following process. In the formula, Bz represents a benzoyl group, Me represents a methyl group, and TBDMS represents a t-butyldimethylsilyl group.

[0041]

Embedded image

Formation of Compound (2) Compound (1) [methyl] was added to 90 ml of a mixed solvent [tetrahydrofuran-methyl alcohol (1: 1)].
2,3,5-tri-O-benzoyl-α-D-arabinofuranoside] was dissolved in 14.3 g (30 mmol), and 540 mg (10 mmol) of sodium methoxide was added thereto.
, And stirred at room temperature overnight, followed by acidic ion exchange resin (Do).
Wex-50w, X-8, manufactured by Dow Chemical Co., Ltd.) for neutralization, and the mixture was filtered. The filtrate was concentrated and methyl α-
4.90 g of D-arabinofuranoside was obtained.

Next, this was dissolved in 100 ml of a mixed solvent [pyridine-methylene chloride (1: 1)], and 3.61 g (30 mmol) of pivaloyl chloride was added to methylene chloride while stirring and cooling with ice under a nitrogen atmosphere. The solution was slowly added dropwise. After allowing this to stand for 3 hours, a solution in which 1.20 g (10 mmol) of pivaloyl chloride was added to methylene chloride was added, and the mixture was stirred overnight. After adding ice and water to the reaction solution and stirring for a while, the reaction solution is concentrated under reduced pressure, water and methylene chloride are added to the residue, and the aqueous layer is further extracted with methylene chloride. Was combined with a methylene chloride layer, washed successively with water, a saturated sodium hydrogen carbonate solution, water and a saturated saline solution, and dried using anhydrous magnesium sulfate.

Next, the residue obtained by distilling off the solvent was dissolved in 100 ml of dimethylformamide, 9.00 g (60 mmol) of t-butyldimethylsilyl chloride and 8.20 g (120 mmol) of imidazole were added, and the mixture was stirred at room temperature overnight. Stirred. This reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The extract was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was dissolved in 150 ml of ether, and stirred under an argon atmosphere, and 1.30 g (34 mmol) of lithium aluminum hydride was added thereto while cooling with ice, and the mixture was stirred and reacted for 3 hours. Further, a cooled saturated ammonium chloride solution was added to the reaction solution to decompose excess reducing agent.

After filtration using Celite, the filtrate was concentrated under reduced pressure to give compound (2) [methyl 2,3-
[Di-O-t-butyldimethylsilyl-α-D-arabinofuranoside] 11.6 g was obtained. This was subjected to silica gel column chromatography [hexane-ethyl acetate (10:
Purified eluate 6.20)
g was obtained (yield 53%).

The physical properties of the compound (2) obtained in this example are as shown in Table 1 below.

[0047]

[Table 1]

Production of compound (3) 4.37 g of oxalyl dichloride in 75 ml of methylene chloride
(34 mmol) was dissolved in dimethylsulfoxide 4.9 while stirring at −78 ° C. under an argon atmosphere.
A solution of 5 g (68 mmol) in 15 ml of methylene chloride was added dropwise, and after stirring for 20 minutes, the compound (2) [methyl 2,3-di-O-t-butyldimethylsilyl-α was added at -70 ° C. -D-arabinofuranoside] 4.5
0 g (12 mmol) of methylene chloride solution (10 ml)
Was added dropwise.

After stirring for 30 minutes, triethylamine 1
3.9 g (136 mmol) was added and the temperature was gradually raised to room temperature. After discharging the reaction solution into ice water, ether extraction was performed, and the extract was subjected to a saturated ammonium chloride solution,
The extract was washed with water and saturated saline in that order, and dried using anhydrous magnesium sulfate.

Then, the solvent was distilled off to remove the compound (3) [methyl 2,3-di-O-t-butyldimethylsilyl-α
-D-arabinopentodialdofuranoside- (1,
4)] 4.46 g was obtained.

The results of infrared absorption spectrum analysis of compound (3) obtained in this example are as follows.

IR ν _max ^film cm ^-1 : 1730.

Production of Compound (4) A solution prepared by dissolving 5.00 g (13 mmol) of Compound (3) in hexane was added dropwise to 250 ml of a hexane solution containing 50 mmol of trimethylaluminum at -78 ° C under an argon atmosphere.

Thereafter, after vigorous stirring was continued for 4 hours, a saturated ammonium chloride solution was added to the reaction solution, and stirring was continued vigorously again for a while. Then, the reaction solution was transferred to ice water, and the insoluble matter was filtered using celite. After separate removal, the filtrate was separated from the organic layer and extracted with benzene.

The extract is combined with the previously separated organic layer,
The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [benzene-ethyl acetate (50:
1)] to give a compound (4) [methyl 6-deoxy-2,3-di-O-t-butyldimethylsilyl-α-
D- altrofuranoside] with the compound shown in Example 3 below (11) [methyl 6 Deo carboxy-2,3--
3.70 g (yield 70%) of a mixture with “Ot-butyldimethylsilyl-β-L-galactofuranoside” was obtained.
Its production ratio was determined to be compound (11): compound (4) = 4: 96 by 1H-NMR spectrum analysis at 500 mHz.

Compound (4) [Methyl 6-deoxy-
2,3-di-O-t-butyldimethylsilyl-α-D-
Altrofuranoside] is obtained by subjecting the above mixture to silica gel column chromatography [hexane-ethyl acetate (1
0: 1)] to separate and purify.

The physical properties of the compound (4) obtained in this example are as shown in Table 2 below.

[0058]

[Table 2]

Production of Compound (5) The above compound (4) [methyl 6-deoxy-2,3-di-Ot-butyldimethylsilyl-α-D-altrofuranoside] (268 mg) dissolved in pyridine (5 ml).
(0.66 mmol) was added with 250 mg (1.3 mmol) of p-toluenesulfonyl chloride (tosyl chloride), and the mixture was stirred at room temperature for almost 200 hours. Next, ice water was added to the reaction solution, the mixture was stirred for a while, and extracted with ether. The extract is water, saturated potassium carbonate solution,
The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
mg (quantitative).

253 mg of monotosylate (0.
45 mmol) with hexamethylphosphoric triamide (HM
PA) dissolved in 5 ml, potassium thioacetate 206 mg
(1.8 mmol) and added under an argon atmosphere.
Stirred at 85 ° C. for 4 hours. After the reaction solution was allowed to cool, it was transferred into water and extracted with ether.

The extract was washed sequentially with water and saturated saline,
It was dried using anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography [hexane / ethyl acetate (10: 1) mixed eluent] to give compound (5) [methyl 5-S-acetyl-
155 mg of a purified product of 6-deoxy-2,3-di-O-t-butyldimethylsilyl-5-thio-β-L-galactofuranoside] was obtained (yield 74%).

The physical properties of the compound (5) obtained in this example are as shown in Table 3 below.

[0063]

[Table 3]

Production of Compound (7) Compound (5) [Methyl 5-S-acetyl-6-deoxy-2,3-di-O-t-butyldimethylsilyl-
5-thio-β-L-galactofuranoside] 80 mg
(0.17 mmol) was dissolved in 1 ml of a mixed solvent [acetic acid-acetic anhydride-concentrated sulfuric acid (15: 15: 1 (volume ratio))].
The mixture was stirred overnight at 0 ° C. to room temperature under an argon atmosphere. After adding sodium acetate powder and ice water to the reaction solution and stirring vigorously for a while, the reaction mixture was transferred into water and extracted with methylene chloride.

The extract was washed successively with water, saturated sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Purification with hexane-ethyl acetate 4: 1) gave compound (6) [1,2,3
-Tri-O-acetyl-5-S-acetyl-6-deoxy-5-thio-L-galactofuranose] 58 mg (97% yield).

Next, this was dissolved in 2 ml of methyl alcohol, 2 mg of sodium methoxide was added while stirring at 0 ° C. under an argon atmosphere, and stirring was continued for 5 hours, and an ion exchange resin (Dowex-50w) was added to the reaction solution. , X-
After neutralization by adding 8), the ion-exchange resin was filtered off and the filtrate was concentrated under reduced pressure to synthesize 12 mg (quantitative) of the desired compound (7) [5-deoxy-5-thio-L-fucopyranose]. did.

The physical properties of the compound (7) obtained in the above example are as follows. m. p. 152 ° C. [methanol] Specific rotation [α] _D ²² -227 ° [H ₂ O]

Example 2 This example shows an example of the production process of [1,5-dideoxy-1,5-imino-L-phthitol], and is based on the following process.

Embedded image

Production of Compound (8) Compound (4) [methyl 6-deoxy-2,3-di-Ot- obtained by the same method as in [Example 1].
Butyldimethylsilyl-α-D-altrofuranoside]
644 mg (1.59 mmol) was dissolved in 5 ml of pyridine, and 273 mg (2.38 mmol) of metasulfonyl chloride (mesyl chloride) was added dropwise with stirring under ice-cooling, and the mixture was stirred overnight. Ice water was added to the reaction solution, the mixture was stirred for a while, and extracted with ether.

The extract was washed successively with water, a saturated sodium hydrogen carbonate solution, water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain monomesylate 7.
62 mg (quantitative) were obtained.

The obtained monomesylate was dissolved in 5 ml of dimethyl sulfoxide, and 308 mg of sodium azide was dissolved.
(4.74 mmol) and 80 under an argon atmosphere.
Stirred at 5.5 ° C. for 5.5 hours. After allowing the reaction solution to cool, it was transferred into water and extracted with toluene.

The extract was washed successively with water and saturated saline,
It was dried using anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography [hexane / ethyl acetate (100: 1) mixed eluent] to give compound (8) [methyl 5-azido-5.
Purified product 583 of 6-dideoxy-2,3-di-O-t-butyldimethylsilyl-β-L-galactofuranoside]
mg (yield 85%).

The physical properties of the compound (8) obtained in this example are as shown in Table 4 below.

[0074]

[Table 4]

Production of Compound (10) The resulting compound (8) [methyl 5-azido-5,6-
Dideoxy-2,3-di-O-t-butyldimethylsilyl-β-L-galactofuranoside] 5.49 g (12.
7 mmol) and the compound (9) [1,2,3-tri-O-acetyl-5] in the same manner as in [Example 1].
-Azido-5,6-dideoxy-L-galactofuranose], 3.90 g (yield 98%), obtained by treating 315 mg (1.0 mmol) of this compound (9) with sodium methoxide. The triol derivative was dissolved in 95% methyl alcohol, and subjected to catalytic reduction at room temperature and normal pressure for 7 hours under a hydrogen atmosphere in which 20 mg of 10% palladium carbon was present.

Next, after filtering the catalyst, the filtrate was concentrated and the residue was subjected to ion exchange chromatography (Dowex-5).
0w, X-8: 1N ammonia water) to give compound (10) [1,5-dideoxy-1,5
-Imino-L-ftitol] 156 mg (83% yield)
I got

Compound (10) obtained in the above Example
Are as follows.

Specific rotation [α] _D ²⁵ -48 ° [C = 0.
2, H ₂ O]

[0079] [Embodiment 3] This embodiment secondarily be prepared compounds in the production method of the present invention [methyl 6 - de <br/> oxy-2,3--O-t-butyldimethylsilyl −
β-L-galactofuranoside] according to the following steps.

[0080]

Embedded image

8 ml of methyl lithium in 13 ml of ether
l (1.1 M ether solution) and 835 mg of copper iodide
Compound (3) obtained in [Example 1] above was stirred in an ether solution of lithium dimethyl cue plate (Me ₂ CuLi) prepared from (4.4 mmol) under an argon atmosphere at -78 ° C. Methyl 2,3-di-
Ot-butyldimethylsilyl-α-D-arabinopentodialdofuranoside- (1,4)] 253 mg (0.
(65 mmol) was added dropwise, and stirring was continued for 2 hours and 30 minutes.

Next, a saturated ammonium chloride solution was added to the reaction solution, and the reaction mixture was extracted with benzene. The extract was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography [Benze-
Ethyl acetate (50: 1)] to give compound (11)
[Methyl 6-deoxy-2,3-di-O-t-butyldimethylsilyl-β-L-galactofuranoside] and the aforementioned compound (4) [methyl 6-deoxy-2,3-di-
[Ot-butyldimethylsilyl-α-D-altrofuranoside] in an amount of 183 mg (yield 70%).
Its production ratio was determined to be compound (11): compound (4) = 92: 8 by ¹ H-NMR spectrum analysis at 500 mHz.

The obtained compound (11) [methyl 6-deoxy-2,3-di-O-t-butyldimethylsilyl-
β-L-galactofuranoside] was separated and purified by subjecting the above mixture to silica gel column chromatography [hexane-ethyl acetate (10: 1)].

The physical properties of the compound (11) obtained in this example are as shown in Table 5 below.

[0085]

[Table 5]

The compound (1) obtained in the present Example
1) Using [methyl 6-deoxy-2,3-di-O-t-butyldimethylsilyl-β-L-galactofuranoside], for example, as shown in the following [Reference Example 1], [L-fucopyranose] Can be manufactured.

Reference Example 1 The above compound (11) [methyl 6-deoxy-2,3-di-O-t-butyldimethylsilyl-β-L-galactofuranoside] 37 mg (0.
09 mmol) was dissolved in 1 ml of a mixed solvent [acetic acid-acetic anhydride-concentrated sulfuric acid (15: 15: 1 (volume ratio))], and the mixture was stirred overnight at 0 ° C. to room temperature under an argon atmosphere. After adding sodium acetate powder and ice water to the reaction mixture and stirring vigorously for a while, the reaction mixture was transferred into water and extracted with methylene chloride, and the extract was treated with water, saturated sodium hydrogen carbonate solution, water, The extract was washed successively with brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography [hexane-ethyl acetate (4: 1)] to give the compound [1, 2,
3,5-Tetra-O-acetyl-L-fucofuranose]
27 mg (90% yield) were obtained.

Next, this was dissolved in 2 ml of methyl alcohol, 2 mg of sodium methoxide was added thereto while stirring at 0 ° C. under an argon atmosphere, and stirring was continued for 5 hours, and an ion exchange resin (Dowex-50w) was added to the reaction solution. , X-
After adding 8) and neutralizing, the ion-exchange resin was separated by filtration and the filtrate was concentrated under reduced pressure to obtain 10 mg (yield: 75%) of [L-fucopyranose].

The specific rotation of L-fucopyranose obtained in Reference Example 1 is as follows.

Specific rotation [α] _D ²¹ −73 ° [C = 1.
1, H ₂ O]

Reference Example 2 The compound (10) obtained in Example 2 [1,5-dideoxy-1,5-imino-L-
Futitol] and the compound (12) [methyl 6-oxohexanoate] are subjected to reductive condensation in a hydrogen atmosphere in the presence of a palladium catalyst to give the compound (13) [1,5-dideoxy-1,5-imino- N- [5- (methoxycarbonyl) pentyl] -L-fucitol] was obtained (for example, [L
iebigs Ann. Chem. , P. 1221, (1
988)], [J. Biol. Chem. , 265
Volume, 16472, (1990)].

This compound was used as an inhibitor of fucosidase, affinity. It can be used as a ligand for chromatography.

[Reference Example 3] The α-form of the compound (13) obtained in Reference Example 2 and the compound (7) obtained in Example 1 were obtained.
The inhibitory activity on L-fucosidase was measured.

The measuring method is as follows. (1) Reaction solution Substrate solution: valanitrophenyl-α-L-fucose, 1
mg / ml, 0.2M citrate-phosphate buffer, pH
4.0, 0.5 M salt Enzyme solution: α-L-fucosidase (Scallop; Charo
Nia Lampas) 200mU / ml, 20m
M ammonium acetate buffer, pH 4.0, 1 mM ZnC
l ₂ compound solution: aqueous solution of various concentrations of 10 mg to 10 μg / ml

(2) Enzyme reaction 10 μl of the compound solution and 50 μl of the enzyme solution were mixed and mixed.
After leaving the mixture at 5 ° C. for 5 minutes, 100 μl of the substrate solution was added to the mixed solution, and the mixture was reacted at 37 ° C. for 15 minutes. The reaction was stopped by adding 2 ml of 1M sodium carbonate. The concentration of liberated paranitrophenol was determined by measuring the absorbance at 420 nm (A
Quantified in i). As a control, the absorbance (Ac) when water was added instead of the compound solution and the absorbance (Ab) of a substrate blank in which the enzyme solution was replaced with an enzyme buffer from this reaction system were determined.

[0096] The inhibitory activity was determined by the method described above. The inhibition ratio I (%) was calculated according to the following equation.

[0097]

(Equation 1)

In the above measurement system, 50% inhibition (I
The amount of the compound giving ₅₀ ) during the enzymatic reaction was 5 μg for the compound (13) and 260 μg for the compound (7).

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 211 / 46,335 / 02 C07H 15/04 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A D-arabinofuranoside derivative represented by the following general formula: (Wherein R1 represents a trialkylsilyl group and R2 represents a lower alkyl group; the same applies hereinafter) with a lower alkyl metal compound, and reacted with a general formula: (Wherein, R3 represents a lower alkyl group; the same applies hereinafter), and the 5-position hydroxyl group is converted to a leaving group by sulfonylation, and then reacted with a thiocarboxylate or an azide compound. And the general formula (Wherein, X represents a lower acylthio group or an azido group; the same applies hereinafter). After acetic acid decomposition, the protective group is removed and the resulting hydroxyl group is acetylated to give the resulting acetyl. A compound of the general formula characterized in that the compound is deacetylated or reduced after deacetylation. (Wherein, R4 represents a hydrogen atom or a hydroxyl group, and Y represents a sulfur atom (S) or an imino group (NH); the same applies hereinafter). 2. A D-arabinofuranoside derivative represented by the following general formula. Embedded image 3. A furanoside derivative represented by the following general formula. Embedded image (In the formula, R ₃ represents a lower alkyl group. The same applies hereinafter.) 4. A furanoside derivative represented by the following general formula. Embedded image (In the formula, R ₃ represents a lower alkyl group. The same applies hereinafter.)