WO2019087810A1 - Production method for 2-deoxy-2-fluoroglucose - Google Patents

Abstract

The present invention is capable of producing a 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoroglucose in high yield by reacting a 1,3,4,6-tetra-O-acyl-2-O-(trifluoromethylsulfonyl)-β-D­manopyranose with hydrogen fluoride in the presence of a specific organic base. Said compound can be easily converted to 2-deoxy-2-fluoroglucose by further conducting a deprotection reaction. Thus, 2-deoxy-2-fluoroglucose can be efficiently produced in an industrial scale.

Description

Method for producing 2-deoxy-2-fluoro-glucose

The present invention relates to a method of producing 2-deoxy-2-fluoro-glucose.

2-Deoxy-2-fluoro-glucose is a useful compound which can be used as a drug substance or an intermediate of a medicine. For example, radioactive fluorine-containing [ ¹⁸ F] -2-fluoro-2-deoxyglucose ([ ¹⁸ F] -FDG) has been used as a molecular probe in positron emission tomography. As a typical production method of 2-deoxy-2-fluoro-glucose, 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose and A method of reacting tetrabutylammonium fluoride (Non-patent document 1), 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose Method of reacting potassium fluoride (Non-patent document 2, Patent document 1) or method of reacting 1,3,4,6-tetra-O-acetyl-β-D-mannopyranose with diethylaminosulfa trifluoride (Non-patent document 3) and a method (non-patent document 4) of reacting 3,4,6-tri-O-acetyl-D-glucal with acetyl hypofluorite

WO 2010/079579

R. W. Binkley. Et al, J. Carbohydrate Chemistry, 6, 1987, 203-219. H. K. Hamacher. Et al, J. Nucl Med., 27, 1986, 235-238. P. Kovac, Carbohydrate Research, 153, 1986, 168-170. M. J. Adam, J. Chem. Soc., Chem. Commun., 1982, 730-731.

Although the method described in Patent Document 1 can be continuously produced by a production apparatus under high temperature and high pressure conditions, the yield of the desired product is low, and it is difficult to separate other byproducts, which is industrial Unfavorable.

The method described in Non-Patent Document 1 has a low yield (23%), and it is difficult to separate the desired product from other by-products, making it difficult as an industrial production method.

The method described in Non-Patent Document 2 requires the use of a stoichiometric amount of an expensive phase transfer catalyst such as Cryptofix K222, and accordingly requires much work in post-treatment and purification steps.

The method described in Non-Patent Document 3 is expensive, and because it uses diethylaminosulfatrifluoride having a risk of explosion, it is limited to small scale synthesis and difficult to be adopted as an industrial production method. It was a thing.

Although the method described in Non-patent Document 4 is mentioned as a seemingly preferable method, it is industrially also from the fact that the reaction temperature is extremely low as -78 ° C., and acetyl hypofluorite has a danger of explosion at high concentration. Is an undesirable method.

An object of the present invention is to provide a method for efficiently producing 2-deoxy-2-fluoro-glucose under industrially practicable conditions.

MEANS TO SOLVE THE PROBLEM In view of the said subject, when the present inventors earnestly examined, 1,3,4,6- tetra-O-acyl -2-O- (trifluoromethyl sulfonyl)-(beta) -D- manno pyranose, Derivatization to 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose by reacting hydrogen fluoride in the presence of an organic base, followed by deprotection of the glucose Found out that 2-deoxy-2-fluoro-glucose can be produced efficiently, and the present invention has been completed.

That is, the present invention provides the inventions described in [Invention 1] to [Invention 9] below.

［式中、Ｒ¹はそれぞれ独立に炭素数が１～８の直鎖状もしくは炭素数３～８の分枝状のアルキル基、または炭素数３～８の環状のアルキル基を表す。］

［式中、Ｒ²、Ｒ³、Ｒ⁴はそれぞれ独立に、炭素数１～１８の直鎖状もしくは炭素数３～１８の分枝状のアルキル基、または炭素数３～１８の環状のアルキル基を表す。］

［式中、Ｒ¹は一般式［１］のＲ¹と同じ。］ [Invention 1]
1,3,4,6-Tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose represented by the general formula [1] is represented by the general formula [2] By reacting hydrogen fluoride in the presence of at least one organic base selected from the following tertiary amines and heterocyclic compounds, the 1,3,4,6- represented by the general formula [3] Method of producing tetra-O-acyl-2-deoxy-2-fluoro-glucose.

[Wherein, each R ¹ independently represents a linear or branched alkyl group having 1 to 8 carbon atoms, or a cyclic alkyl group having 3 to 8 carbon atoms. ]

[Wherein, R ² , R ³ and R ⁴ are each independently a linear or branched alkyl group having 1 to 18 carbon atoms, or a cyclic alkyl having 3 to 18 carbon atoms Represents a group. ]

[In the formula, R ¹ is the same as R ¹ of the general formula [1]. ]

[Invention 2]
The production method according to Invention 1, wherein R ^{1 in the} general formula [1] is a methyl group.

[Invention 3]
The tertiary amine is trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, N, N-dimethylcyclohexylamine, N, N-diethylcyclohexylamine or N, The production method according to Invention 1 or 2, which is N-dimethylbenzylamine.

[Invention 4]
Heterocyclic compounds are pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, N-methylmorpholine, N-methylpiperidine The production method according to Invention 1 or 2, which is 1,4-dimethylpiperazine or 1,2-dimethylimidazole.

[Invention 5]
The process according to any one of Inventions 1 to 4, wherein the molar ratio of the organic base to the hydrogen fluoride is 1: 3 to 100: 1, respectively.

[Invention 6]
An organic solvent is added to a reaction mixture containing 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose represented by the general formula [3] to form a reaction mixture The method according to any one of Inventions 1 to 5, comprising the step of washing the liquid mixture with an aqueous solution of an inorganic base.

[Invention 7]
The method according to invention 6, further comprising the step of adding an acidic aqueous solution to neutralize the inside of the reaction mixture after washing with an aqueous solution of an inorganic base.

[Invention 8]
The production method according to Invention 6 or 7, further comprising the step of concentrating and purifying the reaction mixture containing 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose.

[Invention 9]
After 1,1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose is produced by any method of the invention 1-8, A method for producing 2-deoxy-2-fluoro-glucose represented by the following formula [4] by reacting tetra-O-acyl-2-deoxy-2-fluoro-glucose with a deprotecting agent.

The present invention has the effect of being able to efficiently produce 2-deoxy-2-fluoro-glucose under industrially feasible conditions.

Hereinafter, the present invention will be described in detail. Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments, and can be appropriately carried out based on the ordinary knowledge of the person skilled in the art within the scope of the present invention. can do.

In the present invention, 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose represented by the general formula [1] By reacting hydrogen fluoride in the presence, 1,3,4,6-tetra-O-acyl-2 represented by the general formula [3], which is a protected form of 2-deoxy-2-fluoro-glucose -Deoxy-2-fluoro-glucose is produced.

R ¹ of 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose represented by the general formula [1] is each independently carbon It represents a linear or branched alkyl group having 3 to 8 carbon atoms having 1 to 8 carbon atoms, or a cyclic alkyl group having 3 to 8 carbon atoms. Specific examples of R ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, Examples include n-heptyl group, n-octyl group, cyclohexyl group and the like. Among them, methyl and tert-butyl are preferable, and methyl is particularly preferable. Each of four R ^{1 's} can independently adopt the above-mentioned alkyl group, and among them, it is preferable to adopt all identical alkyl groups. When R ¹ is a methyl group, R ¹ CO represents an acetyl group (Ac), and when R ¹ is a tert-butyl group, R ¹ CO represents a pivaloyl group (Piv).

Examples of 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose represented by the general formula [1] are, for example, H. K. Hamacher , Carbohydrate Research, 128, 1984, 291-295.

As the organic base used in the present invention, a tertiary amine or a heterocyclic compound represented by the general formula [2] is used.

R ² , R ³ and R ⁴ in the tertiary amine represented by the general formula [2] are each independently a straight chain having 1 to 18 carbon atoms or a branched alkyl group having 3 to 18 carbon atoms, Or a cyclic alkyl group having 3 to 18 carbon atoms. Specific examples of tertiary amines are trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, N, N-dimethylcyclohexylamine, N, N-diethylcyclohexyl Examples include amines, N, N-dimethylbenzylamine and the like.

On the other hand, specific examples of the heterocyclic compound include pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, N- Methyl morpholine, N-methyl piperidine, 1,4-dimethyl piperazine, 1,2-dimethyl imidazole and the like can be mentioned. Among them, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5- Lutidine, 2,4,6-collidine, 3,5,6-collidine is preferred. These bases can be used alone or in combination.

The amount of the organic base used is not particularly limited, and it is 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β- represented by the general formula [1]. One mole or more may be used with respect to 1 mole of D-mannopyranose, usually 1 to 20 moles are preferable, and in particular 1 to 10 moles are more preferable.

The amount of hydrogen fluoride used is not particularly limited, and it is 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β- represented by the general formula [1]. to D- mannopyranose 1 mole, fluoride ion (F ^-) as well it is used 0.5 mol or more, usually preferably 0.7 to 50 mol, especially 1 to 30 mol and more preferably.

In the present invention, organic compounds of 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose represented by the general formula [1] are used. The reaction is carried out by reacting hydrogen fluoride in the presence of a base, but “a salt consisting of an organic base and hydrogen fluoride” can be suitably used as a reaction agent, as a fluorine source for substituting a trifluoromethylsulfonyl group with a fluorine atom . That is, utilization of the salt is substantially the same as reacting hydrogen fluoride in the presence of an organic base with respect to the general formula [1]. Therefore, an embodiment in which the fluorination reaction is carried out using “a salt composed of an organic base and hydrogen fluoride” is also considered to be included in the present invention. The “salt comprising an organic base and hydrogen fluoride” may be used in the reaction in combination with the organic base described above.

The organic base in “a salt composed of an organic base and hydrogen fluoride” may be the same as or different from the organic bases described above.

The molar ratio of the organic base to the hydrogen fluoride is in the range of 1: 3 to 100: 1, usually in the range of 1: 3 to 20: 1, preferably in the range of 1: 3 to 3: 1. . For example, “Complex consisting of 1 mole of triethylamine and 3 moles of hydrogen fluoride”, commercially available from Sigma Aldrich, or “Pyridine ̃30% (̃10 mole%) and hydrogen fluoride ̃70% (̃90 mole%) The “complex consisting of) can be used.

Examples of the reaction solvent include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, amide solvents, nitrile solvents, sulfoxide solvents and the like.

Specific examples of these reaction solvents include diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, cyclopentyl methyl ether, n-hexane, n-heptane, n-pentane , N-nonane, n-decane, toluene, xylene, mesitylene, ethylbenzene, methylene chloride, chloroform, 1,2-dichloroethane, ethyl acetate, n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl pyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile, dimethyl sulfoxide and the like can be mentioned.

Among these, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile and dimethyl sulfoxide are preferable, and tetrahydrofuran, N, N-dimethylacetamide is preferable. Formamide and acetonitrile are particularly preferred. These reaction solvents can be used alone or in combination.

The amount of the reaction solvent used is not particularly limited, and it is 1,3,4,6-tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β- represented by the general formula [1]. It is sufficient to use 0.05 L (liter) or more with respect to 1 mol of D-mannopyranose, usually 0.1 to 20 L is preferable, and particularly 0.1 to 10 L is more preferable.

The reaction temperature is not particularly limited, but may be in the range of -100 to + 150 ° C., usually -50 to + 100 ° C., and particularly preferably -20 to + 100 ° C.

The pressure condition is not particularly limited, but may be in the range of atmospheric pressure (0.1 MPa) to 2 MPa (absolute pressure, hereinafter the same in the present specification), and usually 0.1 MPa to 1.5 MPa is preferable. 0.1 MPa to 1 MPa is particularly preferred. Therefore, it is preferable to carry out the reaction using a pressure-resistant reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining).

The reaction time is not particularly limited, but may be in the range of 0.1 to 72 hours, and varies depending on the raw materials and reaction conditions, so the reaction proceeds by analytical means such as gas chromatography, liquid chromatography, NMR and the like. It is preferable to follow the situation and to make an end point when the raw material almost disappears.

By employing the above method, 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose represented by the general formula [3] can be obtained as a crude product. . As post-processing operation, general operation in organic synthesis may be performed. That is, the reaction completed solution is diluted with an organic solvent (eg, toluene, xylene, tert-butyl methyl ether or ethyl acetate), and water or an inorganic base of an alkali metal (eg, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, Or washed with an aqueous solution of potassium carbonate etc. (mainly removal of “salt of trifluorosulfuric acid and organic base”), 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose The reaction mixture (organic phase) containing

In the process of washing with an aqueous solution of an inorganic base, most of the organic base used in the fluorination reaction is contained in the crude product, and if the subsequent steps are continued as such, decomposition products increase and the yield decreases. There is. In such a case, the target product can be obtained with good yield by carrying out the purification step after neutralizing the reaction mixture with an acidic aqueous solution such as an organic acid or inorganic acid. As specific examples of the organic acid mentioned here, formic acid, acetic acid, citric acid, oxalic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, and as specific examples of the inorganic acid, hydrogen chloride, hydrogen bromide, Nitric acid, sulfuric acid and the like can be mentioned.

The crude product of 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose represented by the general formula [2] contained in the concentrated organic phase is optionally By purifying by a method such as activated carbon treatment, column chromatography, recrystallization or the like, highly pure 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose can be obtained.

The 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose represented by the general formula [3] obtained in the present invention is, for example, H. K. Hamacher. Et al. J. Nucl Med., 27, 1986, 235-238. (Non-patent document 2, acidic condition), P. Kovac, Carbohydrate Research, 153, 1986, 168-170. (Non-patent document 3, basic condition) It can be reacted with a deprotecting agent (deprotection reaction) with reference to the method described to easily obtain 2-deoxy-2-fluoro-glucose represented by the formula [4].

As the deprotecting agent used for the deprotecting reaction, it is preferable to use an acid catalyst or a base catalyst. As the acid catalyst, at least one selected from the group consisting of an organic acid, an ion exchange resin and an inorganic acid is selected.

Specific examples of the organic acid include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, PPTS (pyridinium p-toluenesulfonate), 10- A camphor sulfonic acid etc. are mentioned.

On the other hand, examples of the ion exchange resin include Amberlyst H-15, Dowex 50W-X8, and the like, and examples of the inorganic acid include inorganic acids such as hydrochloric acid (hydrogen chloride), hydrobromic acid, sulfuric acid, and phosphoric acid. Among these acid catalysts, hydrochloric acid (hydrogen chloride) and sulfuric acid are preferable, and hydrochloric acid (hydrogen chloride) is particularly preferable.

The amount of the acid catalyst used may be a catalytic amount or more per 1 mol of a high purity product of 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose. The amount is preferably 0.01 to 100 mol, and more preferably 0.03 to 50 mol.

Next, as the base catalyst used for the deprotection reaction, at least one selected from the group consisting of hydrogen carbonate of alkali metal, carbonate of alkali metal, hydroxide of alkali metal, and alkoxide of alkali metal is selected. Be Examples of alkali metal hydrogencarbonates include lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate. Examples of carbonates of alkali metals include lithium carbonate, sodium carbonate and potassium carbonate. Examples of hydroxides of alkali metals include lithium hydroxide, sodium hydroxide and potassium hydroxide. As an alkali metal alkoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide and the like can be mentioned.

Among these base catalysts, alkali metal hydroxides and alkali metal alkoxides are preferable, and sodium methoxide, sodium ethoxide and sodium tert-butoxide are particularly preferable.

The amount of the base catalyst to be used may be a catalytic amount or more per 1 mol of a high purity product of 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose. Is preferably 0.01 to 100 mol, and more preferably 0.03 to 50 mol.

As a reaction solvent, it is preferable to use an alcohol type reaction solvent, and as such a reaction solvent, methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, sec-butanol, tert-butanol Etc.

Among them, methanol, ethanol, n-propanol and n-butanol are preferable, and methanol, ethanol and n-propanol are more preferable. These reaction solvents can be used alone or in combination.

The amount of reaction solvent used is usually 0.1 L or more per mole of high purity product of 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose. 0.1 to 20 L is preferable, and in particular 0.1 to 10 L is more preferable.

The temperature condition is usually −20 to + 100 ° C., preferably −10 to + 80 ° C., and particularly preferably 0 to + 60 ° C.

The reaction time is usually 0.1 to 120 hours, but since it varies depending on the reaction conditions, the progress of the reaction was followed by analytical means such as thin layer chromatography, liquid chromatography, NMR etc. It is preferable to make the time point an end point. The post-treatment is not particularly limited, but usually, the acid catalyst and base catalyst used in excess in the reaction solution and the reaction solvent can be concentrated to recover a high purity white crystalline powder with a good yield. . The desired 2-deoxy-2-fluoro-glucose can be obtained with an even higher chemical purity by subjecting the highly pure white crystalline powder to a purification operation such as activated carbon treatment or recrystallization if necessary.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to these examples. Here, "%" of the analysis value represents "area%" of the composition obtained by measurement by nuclear magnetic resonance spectrum (NMR) or liquid chromatography.

Preparation Example: Preparation of General Formula [1]
150 mL of acetonitrile and 17.6 g (50.5 mmol, 1.0 eq) of 1,3,4,6-tetra-O-acetyl-β-D-mannopyranose and 6.0 g (75.8 mmol, 1.5 eq) of pyridine Were added, 15.7 g (55.6 mmol, 1.1 eq) of trifluoromethanesulfonic anhydride was gradually added under cooling, and the mixture was stirred at 25 ° C. for 2 hours. The conversion of the reaction was 98% as measured by liquid chromatography. The reaction mixture was diluted with 150 mL of tert-butyl methyl ether and washed with 120 mL of water to recover the organic layer. The aqueous layer was further washed with 90 mL of tert-butyl methyl ether. The resulting organic layers were combined and washed once with 90 mL of water. The collected organic layer was concentrated under reduced pressure to obtain 48.8 g of crude crystals. 60 mL of ethanol is added to the crude crystals, heated and dissolved, cooled to 0 ° C., and the precipitated crystals are filtered and vacuum dried to obtain 1,3,4,6-tetra-O-acetyl-2-O- (tri 21.3 g of fluoromethylsulfonyl) -β-D-mannopyranose was obtained. The total yield was 88%.

[Examples 1 to 12] and [Comparative Examples 1 to 4]
General production methods of Examples 1 to 12 and Comparative Examples 1 to 4 are shown below, and the results are summarized in Table 1.

[General manufacturing method]
Acetonitrile 2 mL and 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose 0.96 g (2 mmol, 1.0 eq) and triethylamine • trifluor 0.64 g (4 mmol, 2.0 eq) of a hydride complex and a predetermined amount of an organic base were added, and the mixture was stirred at a predetermined temperature for a predetermined reaction time. The conversion of the reaction was calculated by ¹⁹ F-NMR. The reaction completed solution was diluted with 15 mL of ethyl acetate and washed with 10.83 g of potassium carbonate aqueous solution [prepared from 0.83 g (6.0 mmol, 3.0 eq) of potassium carbonate and 10 mL of water] to recover an organic layer. The aqueous layer was further extracted with 15 mL of ethyl acetate. The resulting organic layers are combined and analyzed by ¹⁹ F-NMR according to the internal standard method (internal standard substance hexafluorobenzene), and it is 1,3,4,6-tetra-O-acetyl-2-deoxy-2- The quantitative yield of fluoro-glucose was calculated.

[Examples 13 to 15]
Next, production methods for Examples 13 to 15 are shown below, and these are also summarized in Table 1.

[Example 13]
Acetonitrile 8 mL and 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose 3.84 g (8 mmol, 1.0 eq) and pyridine. 1.4 g (5.4 mmol, 0.67 eq) of a hydride complex and 4.54 g (42 mmol, 5.3 eq) of 2,6-lutidine were added and stirred at 75 ° C. for 12 hours. The conversion of the reaction was determined by ¹⁹ F-NMR to be 97%. The reaction completed solution was diluted with 20 mL of ethyl acetate and washed with 43.32 g of potassium carbonate aqueous solution [prepared from 3.32 g (24.0 mmol, 3.0 eq) of potassium carbonate and 40 mL of water] to recover an organic layer. The aqueous layer was further extracted with 20 mL of ethyl acetate. The obtained organic layer was analyzed by ¹⁹ F-NMR by an internal standard method (internal standard substance hexafluorobenzene), and it was found that 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose The quantitative yield of was 71%.

Example 14
Acetonitrile 100 mL and 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose 48.0 g (100 mmol, 1.0 eq) triethylamine and trifluorine 32.2 g (200 mmol, 2.0 eq) of hydrogen fluoride complex and 42.9 g (400 mmol, 4.0 eq) of 2,6-lutidine were added and stirred at 75 ° C. for 12 hours. The conversion of the reaction was determined by ¹⁹ F-NMR to be 99%. The reaction completed solution was diluted with 200 mL of toluene and washed with 373.3 g of potassium carbonate aqueous solution [prepared from 37.3 g (270 mmol, 2.7 eq) of potassium carbonate and 336 mL of water] to recover an organic layer. The aqueous layer was further extracted with 100 mL of toluene. The obtained organic layers were combined, washed three times with 100 mL of 1 mol / L hydrochloric acid aqueous solution, and once with 100 mL of water. The obtained organic layer was analyzed by ¹⁹ F-NMR by an internal standard method (internal standard substance hexafluorobenzene), and it was found that 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose The quantitative yield of was 77%. The collected organic layer was concentrated under reduced pressure to obtain 45.0 g of crude crystals. 300 mL of ethanol was added to the total amount of crude crystals, the mixture was heated and dissolved, the temperature was lowered to 0 ° C., and the precipitated crystals were filtered and vacuum dried to obtain 21.0 g of a recrystallized product. The total yield from the reaction to the recrystallization was 60%.

[Example 15]
Acetonitrile 46 mL and 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose 22.2 g (46.2 mmol, 1.0 eq) and triethylamine 14.9 g (92.4 mmol, 2.0 eq) of trihydrogen fluoride complexes and 23.9 g (184.8 mmol, 4.0 eq) of diisopropylethylamine were added and stirred at 50 ° C. for 4 hours. The conversion of the reaction was determined by ¹⁹ F-NMR to be 99%. The reaction completed solution was diluted with 150 mL of toluene and washed with 190.3 g of potassium carbonate aqueous solution [prepared from 17.3 g (125 mmol, 2.7 eq) of potassium carbonate and 173 mL of water] to recover an organic layer. The aqueous layer was further extracted with 100 mL of toluene. The resulting organic layers were combined and washed once with 100 mL of water. The obtained organic layer was analyzed by ¹⁹ F-NMR by an internal standard method (internal standard substance hexafluorobenzene), and it was found that 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose The quantitative yield of was 66%. The collected organic layer was concentrated under reduced pressure to obtain 15.8 g of crude crystals. 100 mL of ethanol was added to the total amount of crude crystals, the mixture was heated and dissolved, the temperature was lowered to 0 ° C., and the precipitated crystals were filtered and vacuum dried to obtain 6.1 g of a recrystallized product. The total yield from the reaction to the recrystallization was 38%.

Example 16 Reaction of General Formula [3] with Deprotecting Agent
30 mL of methanol and 3.0 g (8.6 mmol, 1.0 eq) of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose and 0.09 g (1.7 mmol) of sodium methoxide 0.2 eq) was added and it stirred at 25 degreeC for 30 minutes. Thereafter, ion exchange resin (Amberlite (IR-120)) was added, and the mixture was stirred for 1 hour and filtered. The collected organic layer was concentrated to obtain 1.83 g of crude crystals. Add 18 mL of methanol and heat to dissolve, add 30 mL of ethyl acetate and 30 mL of n-heptane, cool to 0 ° C, filter the precipitated crystals and vacuum dry to obtain 0.70 g of 2-deoxy-2-fluoro-glucose Obtained.
When the obtained 2-deoxy-2-fluoro-glucose is analyzed by ¹⁹ F-NMR by an internal standard method (internal standard substance hexafluorobenzene), the quantitative yield of 2-deoxy-2-fluoro-glucose is 99% Met.

In Examples 1 to 15 using a predetermined organic base (including a salt composed of an organic base and hydrogen fluoride), the desired fluorination reaction proceeds efficiently, and the desired 1,3,4,6-tetra- O-acetyl-2-deoxy-2-fluoro-glucose was obtained in high yield. Also, the obtained 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose can be easily derivatized to 2-deoxy-2-fluoro-glucose by a deprotection reaction. Were confirmed from Example 16. On the other hand, in Comparative Examples 1 to 3 using other organic bases and Comparative Example 4 not using an organic base, the desired fluorination reaction does not proceed efficiently, and 1,3,4,6-tetra- The yield of O-acetyl-2-deoxy-2-fluoro-glucose was low.

[; Reaction with 1,3,4,6-tetra -O- acetyl-beta-D-mannopyranose and Deoxo-Fluor ^TM Reference Example 1]
5 mL of dichloromethane and 1.74 g (5.0 mmol, 1.0 eq) of 1,3,4,6-tetra-O-acetyl-β-D-mannopyranose were added. After cooling the reaction vessel to 0 ° C., and stirred for 15 hours at room temperature was added bis (2-methoxyethyl) amino sulfur trifluoride ^{(Deoxo-Fluor TM) 2.21g (} 10mmol, 2.0eq). The reaction mixture was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated aqueous sodium hydrogen carbonate solution, and the organic layer was recovered. The aqueous layer was further extracted with 30 mL of ethyl acetate. The obtained organic layer was analyzed by ¹⁹ F-NMR by an internal standard method (internal standard substance hexafluorobenzene), and it was found that 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose The quantitative yield of was 11%.

[Reference Example 2; Reaction of General Formula [1] with Metal Fluoride in the Presence of Inorganic Base]
Acetonitrile 8 mL and 1,3,4,6-tetra-O-acetyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose 0.96 g (2 mmol, 1.0 eq) and potassium fluoride 0 .10 g (1.8 mmol, 0.9 eq), 0.06 g (0.4 mmol, 0.2 eq) of potassium carbonate and 20.26 g (2 mmol, 1.0 eq) of 18-crown are added and stirred at 80 ° C. for 2 hours did. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with 10 mL of water, and the organic layer was recovered. The aqueous layer was further extracted with 20 mL of ethyl acetate. The obtained organic layer was analyzed by ¹⁹ F-NMR by an internal standard method (internal standard substance hexafluorobenzene), and it was found that 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-glucose The quantitative yield of was 7%.

The 2-deoxy-2-fluoro-glucose targeted by the present invention can be used as a drug substance or an intermediate of a pharmaceutical.

Claims (9)

1,3,4,6-Tetra-O-acyl-2-O- (trifluoromethylsulfonyl) -β-D-mannopyranose represented by the general formula [1] is represented by the general formula [2] By reacting hydrogen fluoride in the presence of at least one organic base selected from the following tertiary amines and heterocyclic compounds, the 1,3,4,6- represented by the general formula [3] Method of producing tetra-O-acyl-2-deoxy-2-fluoro-glucose.

[Wherein, each R ¹ independently represents a linear or branched alkyl group having 1 to 8 carbon atoms, or a cyclic alkyl group having 3 to 8 carbon atoms. ]

[Wherein, R ² , R ³ and R ⁴ are each independently a linear or branched alkyl group having 1 to 18 carbon atoms, or a cyclic alkyl having 3 to 18 carbon atoms Represents a group. ]

[In the formula, R ¹ is the same as R ¹ of the general formula [1]. ] The manufacturing method of Claim ¹ whose R <1> of General formula [1] is a methyl group. The tertiary amine is trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, N, N-dimethylcyclohexylamine, N, N-diethylcyclohexylamine or N, The production method according to claim 1 or 2, which is N-dimethylbenzylamine. Heterocyclic compounds are pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, N-methylmorpholine, N-methylpiperidine The production method according to claim 1 or 2, which is 1,4-dimethylpiperazine or 1,2-dimethylimidazole. The method according to any one of claims 1 to 4, wherein the molar ratio of the organic base to the hydrogen fluoride is 1: 3 to 100: 1, respectively. An organic solvent is added to a reaction mixture containing 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose represented by the general formula [3] to form a reaction mixture The method according to any one of claims 1 to 5, further comprising the step of washing the liquid mixture with an aqueous solution of an inorganic base. The method according to claim 6, further comprising the step of adding an acidic aqueous solution to neutralize the inside of the reaction mixture after washing with an aqueous solution of an inorganic base. 8. The method according to claim 6, further comprising the step of concentrating and purifying the reaction mixture containing 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose. 9. After producing 1,3,4,6-tetra-O-acyl-2-deoxy-2-fluoro-glucose by the method according to any one of claims 1 to 8, subsequently, said 1,3,4,6 -A method for producing 2-deoxy-2-fluoro-glucose represented by the following formula [4] by reacting -tetra-O-acyl-2-deoxy-2-fluoro-glucose with a deprotecting agent.