JP2021095367A - Method for Producing C-aryl Glycoside Derivative - Google Patents

Abstract

To provide a method that can produce a C-aryl glycoside derivative stably and inexpensively.SOLUTION: A method for producing a C-aryl glycoside derivative includes the step of mixing, for example, in an organic solvent, the following benzyl-protected C-aryl glycoside derivative (IaA), at least one silyl compound selected from trimethylsilyl chloride and trimethylsilyl bromide, and an alkali metal iodide, thereby producing the following C-aryl glycoside derivative (IIaA).SELECTED DRAWING: None

Description

The present invention relates to a novel method for producing a C-aryl glycoside derivative.

The C-aryl glycoside derivative has a structure in which a sugar moiety (glycoside) and a non-sugar moiety (aryl) are connected by a carbon atom, and exhibits various physiological activities.

Examples of the C-arylglycoside derivative include canagliflozin ((2S, 3R, 4R, 5S, 6R) -2-(3-[(5- (4-fluorophenyl) thiophene-2), which is useful as an antidiabetes drug. -Il) -4-methylphenyl] -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol) and the like.

As a method for producing a C-arylglycoside derivative, generally, a compound in which the hydroxyl group of the C-arylglycoside derivative is protected with a benzyl group (Bn) (hereinafter, also referred to as a benzyl-protected C-arylglycoside derivative) is commercially available. A method is carried out in which trimethylsilyl iodide (prepared and once taken out of the reaction system; hereinafter, also referred to as extrasystem TMS-I) is mixed and the benzyl group is eliminated to produce the derivative (hereinafter, also referred to as extrasystem TMS-I). Patent Document 1).

However, the extrasystem TMS-I is poorly stable in water and may gradually decompose unless stored in a strictly controlled dry atmosphere. As described above, there is room for improvement in the above manufacturing method. In addition, extrasystem TMS-I is expensive and accounts for a large proportion of the production cost of the C-arylglycoside derivative.

WO2016 / 128995

G. A. Olah et al. J. Org. Chem. 1979, 44, 8, 1247-1251

By the way, in order to improve the poor stability of the extrasystem TMS-I, trimethylsilyl iodide (hereinafter, also referred to as in-system TMS-I) prepared in the reaction system is not taken out of the reaction system and is subjected to the reaction. It has been studied to use it (Non-Patent Document 1).

For example, a dealkylation reaction of the ether compound as a raw material and an acetonitrile solution containing sodium iodide by adding trimethylsilyl chloride has been studied.

_{However, as a result of the above examination, a hydrolyzate (CH 3} -OH) obtained by decomposing the benzyl group was confirmed from the ether compound having a benzyl group (Compd10 of Table III, CH _3-O-Bn). It has not been.

Even if the above-mentioned hydrolyzate is once produced in the reaction system, it is considered that the hydrolyzate is promptly converted into an iodine compound, as can be seen from the results described in Table IV.

Then, in the reaction system using the in-system TMS-I, it is difficult to remove the benzyl group from the benzyl group-containing ether compound to obtain a hydrolyzate. Therefore, no one could have imagined a configuration in which the in-system TMS-I was used for the debenzylation reaction using the benzyl group-containing ether compound as the raw material compound (substrate).

Therefore, an object of the present invention is to provide a method capable of producing a C-aryl glycoside derivative stably and inexpensively.

Under such circumstances, the present inventors have conducted diligent studies in order to solve the above problems.

Then, in Non-Patent Document 1, the reason why the hydrolyzate of the benzyl group-containing ether compound is not obtained and the iodine compound is obtained affects the raw material compound (substrate) that undergoes the debenzylation reaction. I thought it might be. That is, we considered that a hydrolyzate could be obtained if the molecular structure of the substrate was different, and examined the substrate. As a result, it was found that when the in-system TMS-I was allowed to act on a compound having a specific skeleton, specifically, a benzyl-protected C-arylglycoside derivative, the debenzylation reaction proceeded effectively, and the present invention was found. Has been completed.

That is, the present invention
In an organic solvent,
The following formula (Ia)

[In the formula, R ¹ is an alkyl group, an alkoxy group, an alkoxyalkyl group, an aralkyl group, or a halogen atom, n is an integer of 0 to 4, and when n is 2 or more, it is the same group. It may be a different group, Bn is a benzyl group, and Ar is an aromatic ring group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Is. ]
A benzyl-protected C-aryl glycoside derivative represented by
With at least one silyl compound selected from trimethylsilyl chloride and trimethylsilyl bromide,
Alkali metal iodide and
By mixing
The following formula (IIa)

^{Wherein, R} 1, n, and Ar has the same meaning as in formula (Ia). ]
This is a method for producing a C-aryl glycoside derivative, which comprises producing the C-aryl glycoside derivative represented by.

According to the present invention, a C-aryl glycoside derivative can be stably produced. Further, the present invention is an efficient method in terms of cost related to the reactant because it does not use extrasystem TMS-I, and is industrially beneficial.

The present invention is a method for producing a C-aryl glycoside derivative by mixing a specific benzyl-protected C-aryl glycoside derivative, a specific silyl compound, and a specific iodide.

<Benzyl-protected C-aryl glycoside derivative>
In the present invention, the benzyl-protected C-aryl glycoside derivative used as a substrate (raw material) is represented by the following formula (Ia).

[In the formula, R ¹ is an alkyl group, an alkoxy group, an alkoxyalkyl group, an aralkyl group, or a halogen atom, n is an integer of 0 to 4, and when n is 2 or more, it is the same group. It may be a different group, Bn is a benzyl group, and Ar is an aromatic ring group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Is. ] Is a compound represented by.

In the present invention, the benzyl-protected C-aryl glycoside derivative can be produced by a known method, that is, the method described in the patent document. Moreover, if a commercially available product exists, it can be used.

According to the method described in the patent document, the benzyl-protected C-arylglycoside derivative is a β-form (compound represented by the above formula (Ia)): α-form (isomer of the compound represented by the above formula (Ia)). Body) = 8: 2 (molar ratio) is obtained as a mixture containing the mixture. The α-form cannot be the target C-aryl glycoside derivative even if it is subjected to a debenzylation reaction. As a matter of course, in the present invention, a benzyl-protected C-aryl glycoside derivative containing such an isomer (α-form) can also be used as a substrate (raw material). When such a mixture is used, the target hydrolyzate represented by the following formula (IIa) (hereinafter, also referred to as hydrolyzate (IIa)) and the α-form benzyl group are eliminated. A mixture of a hydrolyzate (hereinafter, also referred to as a hydrolyzate (IIb)), which is a compound that has become a hydroxyl group, is obtained. In the present invention, as will be described later, the target hydrolyzate (IIa) can be separated and purified from the mixture of these hydrolysates by a known means. When a mixture of α-form and β-form is used as the substrate (raw material), the total amount is taken as the amount of substrate used (mass, number of moles).

Further, as described above, the isomer (α-form) cannot become the target C-aryl glycoside derivative (hydrolyzed product (IIa)) even if the debenzylation reaction is carried out. Therefore, the α-form may be removed from the mixture of the α-form and the β-form in advance before the debenzylation reaction is carried out, and the β-form may be separated and purified before use. Examples of the method for separating and purifying the β-form include known methods such as recrystallization, column purification, and reprecipitation.

[Explanation of ^{R 1]}
In the formula (I), R ¹ is an alkyl group, an alkoxy group, an alkoxyalkyl group, an aralkyl group, or a halogen atom.

The ^{alkyl group of R 1} is preferably an alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group and a propyl group.

The ^{alkoxy group of R 1} is preferably an alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, and a propoxy group.

The ^{alkoxyalkyl group of R 1} is preferably an alkoxyalkyl group having 2 to 6 carbon atoms, and specifically, -CH _2- O-CH ₃ , -CH _{2 -CH 2-} O-CH ₃ , -CH. _{2 -CH 2 -CH 2 -O-CH} 3, -CH (-CH 3) -CH 2 -O-CH 3, -CH 2 -O-CH 2 -CH 3, -CH 2 -CH 2 -O- CH _2- CH _{3 and the} like can be mentioned.

As the ^{aralkyl group of R 1} , a phenyl group − an alkylene group having 1 to 3 carbon atoms is preferable, and specific examples thereof include a benzyl group and a phenylethyl group.

Examples of the halogen atom of R ¹ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Further, in the above formula (Ia), n is an integer of 0 to 4, and when n is 2 or more, R ¹ may be the same group or a different group. When n is 1 or 2, the compound represented by the formula (Ia) is particularly useful as a synthetic intermediate for drug substance such as an antidiabetic drug. Therefore, n is preferably 1 or 2.

In the above formula (Ia), when n is 2, the positions where the two R ^1s are bonded are preferably the 4-position and the 6-position of the benzene ring. The 1st position of the benzene ring is the position where the sugar moiety (glycoside) is bonded.

In the formula (Ia), when n is 2, a combination of two of R ¹ is preferably a combination of two groups selected from the alkyl group, and the alkoxy group. More preferably, the 4-position of the benzene ring is an alkyl group and the 6-position of the benzene ring is an alkoxy group. More preferably, the 4-position of the benzene ring is a methyl group and the 6-position of the benzene ring is a methoxy group.

[Explanation of Ar]
In the formula (Ia), Ar is an aromatic ring group which may have a substituent or an aromatic heterocyclic group which may have a substituent.

The aromatic ring group of Ar is a 1 to 4 ring type, preferably a 1 to 3 ring type, and more preferably a 1 or 2 ring type aromatic ring group. The number of ring-constituting carbons in the aromatic ring group is 6 to 18, preferably 6 to 14, and more preferably 6 to 10. The aromatic ring group may be a monocyclic (single-ring) aromatic ring group or a condensed polycyclic aromatic ring group. In the case of a condensed polycyclic group, the aromatic ring group may be a partially saturated condensed polycyclic aromatic ring group.

The number of substituents that the aromatic ring group of Ar can have can be appropriately determined according to the number of carbon atoms, the number of members, and the like of the aromatic ring group. The number of substituents that the aromatic ring group can have is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.

The aromatic heterocyclic group of Ar is an aromatic heterocyclic group having a 1 to 4 ring type, preferably a 1 to 3 ring type, and more preferably a 1 or 2 ring type. The number of heteroatoms contained in the aromatic heterocyclic group is 1 to 4, preferably 1 to 3, and even more preferably 1 or 2. The number of members of the aromatic heterocyclic group is preferably 5 to 14 members, more preferably 5 to 10 members. The number of ring-constituting carbon atoms in the aromatic heterocyclic group is appropriately determined according to the number of heteroatoms and the number of members of the aromatic heterocyclic group. In the aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group.

The aromatic heterocyclic group of Ar may be a monocyclic (single-ring) aromatic heterocyclic group or a condensed polycyclic aromatic heterocyclic group.

The number of substituents that the aromatic heterocyclic group of Ar can have can be appropriately determined according to the number of carbon atoms, the number of members, and the like of the aromatic heterocyclic group. The number of substituents that the aromatic heterocyclic group can have is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.

Ar is preferably a group represented by the following formula (Ar-1), (Ar-2) or (Ar-3).

Formula (Ar-1), the (Ar-2) and ^{(Ar-3), R 2} , R 3, and ^{R 4} is an alkyl group, a cyclic ether group, or an optionally substituted phenyl group Is.

Examples of the alkyl group of R ^{2, R 3,} and ^{R 4,} preferably an alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group and a propyl group.

Examples of the cyclic ether group of R ^{2, R 3,} and ^{R 4,} preferably a cyclic ether group having 3 to 5 carbon atoms. Specific examples thereof include 2-oxetanyl group, 3-oxetanyl group, 2-tetrahydrofuranyl group, 3-tetrahydrofuranyl group and 2-tetrahydropyranyl group.

As the phenyl group which may have the above-mentioned substituents of ^{R 2} , R ³ and R ^{4, a phenyl group having a halogen atom is preferable.} Specific examples thereof include a phenyl group having a fluorine atom.

In the formula (Ar-1), s is an integer of 0 to 3, preferably 1. R ² is preferably a phenyl group which may have a substituent. More preferably, it is a phenyl group having a halogen atom. Even more preferably, it is a phenyl group having a fluorine atom. The position where the phenyl group, which may have a substituent, is bonded is preferably the 5-position of the thiophene ring. Then, in the phenyl group having a halogen atom, the position where the halogen atom is bonded is preferably the 4-position of the benzene ring.

When Ar is a group represented by the above formula (Ar-1), it is preferably 5- (4-fluorophenyl) thiophen-2-yl represented by the following formula (Ar-1-1).

In the formula (Ar-2), t is an integer of 0 to 5, preferably 1. R ³ is preferably an alkyl group having 1 to 6 carbon atoms and a cyclic ether group having 3 to 5 carbon atoms. More preferably, it is a methyl group, an ethyl group, or a 3-tetrahydrofuranyl group. The ^{position where −OR 3} is bonded is preferably the 4-position of the benzene ring.

When Ar is a group represented by the above formula (Ar-2), 4-methoxyphenyl represented by the following formula (Ar-2-1) and 4 represented by the following formula (Ar-2-2). It is preferably −ethoxyphenyl or 4-[((3S) -oxolan-3-yl) oxy] phenyl represented by the following formula (Ar-2-3).

In the formula (Ar-3), u is an integer of 0 to 4, preferably 0.

When Ar is a group represented by the above formula (Ar-3), it is preferably a benzothiophen-2-yl represented by the following formula (Ar-3-1).

[Suitable benzyl-protected C-aryl glycoside derivative]
To exemplify a benzyl-protected C-aryl glycoside derivative that is particularly suitable for producing a more useful C-aryl glycoside derivative in the present invention, the benzyl-protected C-represented by the following formulas (IaA) to (IaE) will be illustrated. Aryl glycoside derivatives can be mentioned.

<Cyril compound>
In the present invention, the silyl compound used is not particularly limited as long as it is at least one silyl compound selected from trimethylsilyl chloride and trimethylsilyl bromide.

These silyl compounds may use trimethylsilyl chloride and trimethylsilyl bromide alone or in combination of both. In particular, it is preferable to use trimethylsilyl chloride alone from the viewpoint of reactivity of alkali metal with iodide.

As these silyl compounds, commercially available ones sold as reagents can be used.

In the present invention, the amount of the silyl compound used is not particularly limited, but is preferably 4 to 30 mol, more preferably 4 to 20 mol, based on 1 mol of the benzyl-protected C-aryl glycoside derivative. Is.

<Iodide>
In the present invention, the iodide used is not particularly limited as long as it is an alkali metal iodide. Therefore, known compounds can be used. Specific examples of iodide include lithium iodide, sodium iodide, potassium iodide and the like.

As these iodides, commercially available ones sold as reagents can be used.

Among these iodides, it is preferable to use sodium iodide from the viewpoint of reactivity with the silyl compound.

In the present invention, the amount of iodide used is not particularly limited, but is preferably 4 to 30 mol, more preferably 4 to 20 mol, based on 1 mol of the benzyl-protected C-aryl glycoside derivative. Is. Among them, the molar number is preferably 1 to 4 times, more preferably 1 to 3 times, the number of moles of the silyl compound. The mechanism is unknown, but as shown in the examples, the yield tends to be improved by using 1 times mol or more, preferably more iodide than the silyl compound.

<Organic solvent>
In the present invention, it is preferable to use a reaction solvent in order to smoothly mix the C-aryl glycoside derivative, the silyl compound, and the iodide.

The type of organic solvent used is not particularly limited. Above all, in order to react each component efficiently, nitriles such as acetonitrile and propionitrile or ketones such as acetone, methyl ethyl ketone and diethyl ketone are preferable.

The amount of the organic solvent used is not particularly limited as long as the reaction system can be sufficiently stirred. Above all, in order to efficiently mix each component, it is preferable to use an organic solvent in an amount of 1 to 50 mL with respect to 1 g of the benzyl-protected C-aryl glycoside derivative.

<Mixing of benzyl-protected C-aryl glycoside derivative, silyl compound, and iodide>
In the present invention, the benzyl-protected C-aryl glycoside derivative is reacted with the silyl compound and the iodide. The reaction can be carried out by mixing each component.

The method of mixing each component is not particularly limited, and can be carried out in a reaction vessel equipped with a stirrer.

The procedure for adding each component into the reaction vessel is not particularly limited. From the viewpoint of operability, a method of mixing the benzyl-protected C-aryl glycoside derivative and the iodide and then mixing the silyl compound is preferable. Each of these components may be mixed, if necessary, diluted with an organic solvent.

The temperature and time for mixing each component are not particularly limited, and can be appropriately determined while checking the reaction ratio of the raw material mixture.

Specifically, it can be mixed in a temperature range of −10 to 40 ° C. for 1 to 72 hours.

When the silyl compound is mixed after mixing the benzyl-protected C-arylglycoside derivative and the iodide, the temperature of the mixture containing the benzyl-protected C-arylglycoside derivative and the iodide is -10 to 10. The temperature range was 10 ° C., preferably -5 to 5 ° C., and the entire amount of the silyl compound was added to the mixture so as to maintain the above temperature range, and the obtained mixture was added to the mixture at 10 to 40 ° C., preferably 15 to 40 ° C. It is preferable to raise the temperature to a temperature range of 30 ° C. and mix for 10 to 72 hours, preferably 17 to 48 hours while maintaining the temperature range.

This is preferable because the in-system TMS-I can be efficiently prepared and the debenzylation reaction can proceed in good yield.

The pressure at the time of mixing is also not particularly limited. Specifically, it may be carried out under any atmosphere of atmospheric pressure, reduced pressure, and pressurized. Considering operability, it is preferable to carry out under atmospheric pressure. Further, the atmosphere at the time of mixing is not particularly limited. Specifically, it can be carried out in an air atmosphere and in an atmosphere of an inert gas such as nitrogen or argon. In order to allow the reaction to proceed more stably, it is preferable to carry out the reaction in an atmosphere of an inert gas such as nitrogen or argon.

<Post-treatment; Separation and purification of C-aryl glycoside derivatives>
In the present invention, it is preferable to carry out the following post-treatment after <mixing of a benzyl-protected C-aryl glycoside derivative, a silyl compound and an iodide>.

For example, after the mixing, an aqueous solution such as an aqueous thiosulfate solution is added to the reaction solution, and the product is extracted with an organic solvent. Next, the obtained organic solvent layer is separated and concentrated to separate and purify the C-aryl glycoside derivative. By doing so, the following equation (IIa)

The C-aryl glycoside derivative represented by is can be obtained. In the above formula ^{(IIa), R 1, n} , and Ar have the same meanings as those in formula (Ia), preferred groups are also the same as in formula (Ia).

The obtained C-aryl glycoside derivative can be further separated and purified by known means such as recrystallization, column purification, and reprecipitation. In the present invention, it is a debenzylated hydrolyzate. This is surprising from the description of Non-Patent Document 1 in which a hydrolyzate cannot be obtained and an iodine compound can be obtained.

As described above, when a benzyl-protected C-aryl glycoside derivative containing an α-form and a β-form is used as a substrate (raw material), a compound in which the benzyl group of the β-form, which is the target product, is eliminated to become a hydroxyl group ( Along with the hydrolyzate (IIa)), a compound (hydrolyzate (IIb)) in which the benzyl group of the α-form is eliminated to become a hydroxyl group is by-produced as an impurity. In this case as well, the hydrolyzate (IIb) can be removed and the target hydrolyzate (IIa) can be obtained by using the purification method as described above.

A suitable example of the production method of the present invention is shown below by a reaction formula.

The compound (IIaA) is canagliflozin, the compound (IIaB) is dapagliflozin, the compound (IIaC) is ipragliflozin, the compound (IIaD) is luseogliflozin, and the compound (IIaE) is empagliflozin. Glyflozin. All of these are anti-diabetic drugs.

By performing the above method, a C-aryl glycoside derivative can be stably produced.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto, but is a specific example.

[Example 1]
This is an example of producing a C-aryl glycoside derivative (compound (IIaA)) from a benzyl-protected C-aryl glycoside derivative (compound (IaA)) represented by the following formula.

<Mixing of benzyl-protected C-aryl glycoside derivative, silyl compound, and iodide>
Under an argon atmosphere, (2R, 3R, 4R, 5S, 6S) -3,4,5-tris (benzyloxy) -2- (benzyloxymethyl) -6- (3-((5- (4-fluorophenyl) ) Thiophen-2-yl) methyl) -4-methylphenyl) tetrahydro-2H-pyran (100 mg, 0.0124 mmol; benzyl protected C-arylglycoside derivative (compound IaA)) and acetonitrile (3 mL; organic solvent) , And sodium iodide (190 mg, 0.124 mmol; iodide) was added thereto at 25 ° C. The temperature of the obtained mixture is set to 0 ° C., and trimethylsilyl chloride (0.186 mL, 0.124 mmol; silyl compound) is slowly added therein so that the temperature of the mixture is in the temperature range of 0 to 5 ° C. Added. Then, the temperature of the obtained mixed solution was raised to 25 ° C., and the mixture was stirred as it was for 24 hours.

<Post-processing>
After the stirring, a saturated aqueous sodium thiosulfate solution (10 mL) was added to the obtained reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The ethyl acetate layer obtained by the liquid separation operation was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By purifying the concentrated residue with a silica gel column (eluting solvent; methanol / dichloromethane = 1/30 to 1/20), (2S, 3R, 4R, 5S, 6R) -2- (3-((5- (4)) -Fluorophenyl) Thiophen-2-yl) Methyl) -4-Methylphenyl) -6- (Hydroxymethyl) Tetrahydro-2H-Pyran-3,4,5-Triol (36 mg, 64% yield; C-arylglycoside) A derivative (compound IIaA) was obtained.

^{The analysis results of 1} H-NMR and ¹³ C-NMR of the obtained C-aryl glycoside derivative (compound (IIaA)) are shown below.

^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) 7.61-7.57 (m, 2H), 7.27 (d, J = 4.4 Hz, 1H), 7,22-7.10 (m, 5H), 6.79 (d, J = 3.6Hz, 1H), 4.99 (br, 2H, OH), 4.79 (br, 1H, OH), 4.45 (br, 1H, OH) 4.15 (d, J = 16Hz, 1H), 4.09 (d, J = 16Hz, 1H), 3.96 (d, J = 9.6Hz, 1H), 3.69 (d, J = 11.2Hz, 1H), 3.46-3.41 (m, 1H), 3.29-3.14 (m, 4H), 2.26 (s, 3H)
¹³ C-NMR (101 _{MHz, DMSO-d 6} ) 161.4 (d, J = 243 Hz), 143.63, 140.22, 138.21, 137.35, 134.93, 130.53 (d, J) = 3.1 Hz), 129.65, 129.05, 126.95 (d, J = 8 Hz), 126.34, 126.23, 123.38, 115.86 (d, J = 21.6 Hz), 81.31, 81.17, 78.48, 74.68, 70.44, 61.45, 33.44, 18.79
[Example 2]
The same operation as in Example 1 was carried out except that the amount of sodium iodide used was 380 mg (0.248 mmol).

As a result, (2S, 3R, 4R, 5S, 6R) -2-(3-((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) ) Tetrahydro-2H-pyran-3,4,5-triol (40 mg, 72% yield; C-arylglycoside derivative (compound (IIaA))) was obtained.

Claims (4)

In an organic solvent,
The following formula (Ia)

[In the formula, R ¹ is an alkyl group, an alkoxy group, an alkoxyalkyl group, an aralkyl group, or a halogen atom, n is an integer of 0 to 4, and when n is 2 or more, it is the same group. It may be a different group, Bn is a benzyl group, and Ar is an aromatic ring group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Is. ]
A benzyl-protected C-aryl glycoside derivative represented by
With at least one silyl compound selected from trimethylsilyl chloride and trimethylsilyl bromide,
Alkali metal iodide and
By mixing
The following formula (IIa)

^{Wherein, R} 1, n, and Ar has the same meaning as in formula (Ia). ]
A method for producing a C-aryl glycoside derivative, which comprises producing the C-aryl glycoside derivative represented by. The method for producing a C-aryl glycoside derivative according to claim 1, wherein the benzyl-protected C-aryl glycoside derivative is mixed with the iodide of the alkali metal, and then the silyl compound is mixed. The method for producing a C-aryl glycoside derivative according to claim 1 or 2, wherein the organic solvent is a nitrile-based organic solvent. The method for producing a C-aryl glycoside derivative according to any one of claims 1 to 3, wherein the mixing is carried out in a temperature range of −10 to 40 ° C.