JP2824572B2 - Isotope-labeled aldononitrile derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] [0001] The present invention relates to a method for removing a carbon atom at the 1-position.
¹¹C,¹³C or¹⁴Labeled with an isotope of the carbon atom C
Element-labeled aldononitrile derivatives. Isotope
Labeled 2-deoxyglucose is used for glucose metabolism in vivo.
Is useful for research and clinical diagnosis of
A halogenated aldononitrile derivative can be used in such 2-deoxy
It is useful as an intermediate for producing glucose. [0002] 2. Description of the Related Art Isotopically labeled 2-deoxyglucose
Conventionally, the production method of 2,3: 4,5-di-O-I
Of the hydroxyl group at position 1 of isopropylidene-D-arabinitol
Reactive derivatives, for example, O-trifluoromethylsulfo
The isocyanate-labeled cyanide compound is reacted with
In addition, methods for reduction and hydrolysis are known. Only
According to this method, the intermediate isotope-labeled alcohol
The yield of dononitrile derivatives is extremely low, and
The yield of targeted 2-deoxyglucose is also low. example
For example, 2,3: 4,5-di-O-isopropylidene-1-O-
Trifluoromethylsulfonyl-D-arabinitol and
2-deoxy-3,4: 5, by reaction with sodium anide
6-di-O-isopropylidene-D-glucononitrile
Is only 21%, and the starting compound
Since the reactive derivative of the 1-position hydroxyl group is unstable,
There is also a problem that must be synthesized at the time of use. [0003] DISCLOSURE OF THE INVENTION The present invention relates to the method of
For the production of 2-deoxyglucose labeled with isotopes
To solve the above-mentioned problems.
Isotope labeling with high yield in a short time with simple operation
Intermediate capable of producing 2-deoxyglucose
Isotope-labeled aldononitrile derivatives useful as
The purpose is to provide. [0004] SUMMARY OF THE INVENTION An isotope marker according to the present invention.
The first of the aldononitrile derivatives is represented by the general formula (I) [0005] Embedded image (Where:^*C is¹¹C,¹³C or¹⁴Show C
And OR¹, OR^Two, OR^ThreeAnd OR^FourIndicates a protected hydroxyl group
You. ). [0007] Isotopically labeled aldononitriles according to the present invention
The second derivative of the general formula (II) [0008] Embedded image (Where:^*C is¹¹C,¹³C or¹⁴Show C
And OR¹, OR^Two, OR^ThreeAnd OR^FourIndicates a protected hydroxyl group
X is an alkanesulfonyl group, an arenesulfonyl group
Or an alkylthiothiocarbonyl group. )
It is. [0010] BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I) or (II),
Of isotope-labeled aldononitrile derivatives
And OR¹, OR^Two, OR^ThreeAnd OR^Four Indicates a protected hydroxyl group
Here, as the protecting group for the hydroxyl group, for example,
Trial such as tylsilyl group and t-butyldimethylsilyl group
Acyl such as ruquilsilyl group, acetyl group and benzoyl group
Group, alkoxymethyl group such as methoxymethyl group, benzyl
And the like. Also, the protecting group is adjacent
When it is a protecting group for a hydroxyl group on carbon, R¹And R^TwoYa
T, R^ThreeAnd R^FourMay combine with each other to form a ring,
Such protecting groups include, for example, isopropylidene
Group, ethylidene group, benzylidene group, etc.
Wear. Of these protecting groups, it is easy after the required reaction
Those which can be eliminated are preferable, and particularly, a benzyl group and
An isopropylidene group is preferred. An isotope-labeled aldonitrile according to the present invention
The derivative (I) is represented by the general formula (II) [0012] Embedded image (Where:^*C, OR¹, OR^Two, OR^ThreeAnd OR^FourIs
X is an alkane sulfonyl group, an array
Represents a sulfonyl group or an alkylthiothiocarbonyl group.
You. A) a sulfonyl derivative or dithiocarbo
Acid derivatives were obtained, and Raney nickel, nickel
In the presence of a catalyst such as Kel-aluminum alloy or palladium
Is heated with organic acids such as formic acid and acetic acid to reduce and hydrolyze
Thus, 2-deoxyglu represented by the formula (III)
You can get a course. [0014] Embedded image Sulfonyl represented by the above general formula (II)
In order to obtain a derivative, the isotope represented by the aforementioned general formula (I)
Element-labeled aldononitrile derivatives are generally
Known as a reagent for converting hydroxyl groups to sulfonyl groups
Sulfonylating agents such as methanesulfonyl chloride
Halogenated alkaloids such as toluene, ethanesulfonyl chloride, etc.
Sulfonyl chloride, p-toluenesulfonyl chloride, p-toluene chloride
-Halogenated arrays such as bromobenzenesulfonyl, etc.
React with the sulfonyl. By this reaction,
A phonyl derivative can be obtained. Reaction for obtaining this sulfonyl derivative
Is a suitable organic solvent such as diethyl ether,
In solvents such as isopropyl ether, benzene, and toluene
, Pyridine, triethylamine, sodium carbonate, charcoal
Salts such as potassium acid, sodium hydroxide and potassium hydroxide
Performed in the presence of a group. Sodium hydroxide as base
When using an aqueous solution such as
Reaction in the presence of a phase transfer catalyst such as ammonium
Thus, the reaction time can be shortened. Also, anti
The reaction temperature is usually a temperature in the range of 0 to 100 ° C. Further, instead of the sulfonyl derivative,
Before obtaining the thiothiothiocarboxylic acid ester derivative,
Aldononitrile derivatives such as sodium hydroxide
Reaction of carbon disulfide in the presence of alkali,
With alkyl halides such as methyl iodide and ethyl iodide.
To be killed. Further, the alkylthiothiocarboxylic acid
In the case of ester derivatives, this is
And reduced by the general formula (IV) [0018] Embedded image (Where:^*C, OR¹, OR^Two, OR^ThreeAnd OR^FourIs
Same as above. 2-deoxyglucose represented by)
Obtaining a nonitrile derivative, reducing and hydrolyzing it
Can also obtain 2-deoxyglucose.
You. Sulfonyl represented by the above general formula (II)
Derivative or alkylthiothiocarboxylate derivative
After removing the protecting group of the protected hydroxyl group,
It is preferred to perform a reduction of the group. From this point of view,
The protecting group is preferably, for example, an isopropylidene group. Immediately
The isopropylidene group has a sulfonyl ester group.
Because it can be removed without hydrolyzing.
You. Next, the general formula (I) according to the present invention is represented by the following formula:
The isotope-labeled aldononitrile derivative
According to the description, the general formula (V) [0022] Embedded image (Where, OR¹, OR^Two, OR^ThreeAnd OR^FourIs
Is the same. Arabinose derivatives represented by
Equation (VI) Y-^*CN (VI) (Where^*C is the same as above, and Y is a hydrogen atom or
Indicates a lukari metal atom. ) Isotope labeling
Reaction of hydrogen anhydride or alkali metal cyanide and condensation
Can be obtained. The above alkali gold
As a genus, for example, lithium, sodium, or potassium
Is preferred. This reaction is carried out by using an appropriate organic solvent, for example,
Tanol, ethanol, methyl cellosolve, diethyl ether
-Tel, diisopropyl ether, tetrahydrofura
, Dioxane, dimethylformamide, benzene,
Represented by the above general formula (V) for ruene, xylene, cumene, etc.
Arabinose derivative to be dissolved, and
An isotope-labeled hydrogen cyanide or silicon represented by the formula (VI)
Add an aqueous solution of alkali metal anhydride and stir
Performed. The above reaction is usually carried out at a temperature of about 0 to 50 ° C.
Done in degrees. The reaction time depends on the pH of the reaction solution and
Normally about 1 minute to 1 hour, depending on the solvent
It is. However, in particular, isotope-labeled alkali cyanide
Isotopes in metals¹¹When the half-life is short like C
The reaction time is preferably about 1 to 10 minutes. Further, according to the method of the present invention, the arabic
North derivative and the isotope-labeled hydrogen cyanide or shear
Methanesulfonyl chloride
, P-toluenesulfonyl chloride, p-bromoben chloride
Alkanesulfonyl halides such as zensulfonyl and the like
Arene sulfonyl or halogenated carbon disulfide
Using a phase transfer catalyst in the presence of an alkyl halide.
In this case, the above-mentioned general formula
Sulfonyl derivative or alkylthio represented by (II)
Thiocarboxylic acid ester derivatives can be obtained. The thus obtained general formula (I)
An isotope-labeled aldononitrile derivative represented by
The sulfonyl derivative represented by the general formula (II) or
The alkylthiothiocarboxylic acid ester derivative is usually 2
Is a mixture of optical isomers for the carbon atom at position 1. this
Are separated or separated into the respective optical isomers.
Use it in the next step as described above
Can be. [0028] As described above, the isotope mark according to the present invention is
Aldnonitrile derivatives can be easily and quickly manufactured
And the isotope-labeled aldonitrile
Derivatives can be readily and quickly converted to isotopically labeled 2-deoxyg
Can lead to Lucas. Therefore, the present invention
The element-labeled aldononitrile derivative is, for example, a 1-position carbon
Element¹¹Good for the production of 2-deoxyglucose labeled with C
It can be used appropriately. [0029] EXAMPLES The present invention will be described below with reference to examples.
The present invention is not limited by these examples.
No. Embodiment 1 1.47 g of sodium cyanide was added to a 0.5 M phosphate buffer (p
H7.7) Dissolve in 20 mL and adjust to pH 7.9 with 3M acetic acid.
After adjustment, 2,3: 4,5-di-O-isopropylidene
-2.3 g of D-arabinose diisopropyl ether
(20 mL) solution was added and stirred at room temperature for 10 minutes. After separating the organic layer, the aqueous layer was extracted with ether.
The extract is combined with the organic layer, washed with water,
Dried over sodium acid. The solvent is distilled off under reduced pressure.
The residue was recrystallized from ether / petroleum ether to give 3,4: 5,6
-Di-O-isopropylidene-D-glucononitrile
55 g were obtained as colorless needle crystals. Melting point 82-84 ° C. ¹H-NMR (CDCl_Three, δ) 1.37 (3H, s, CH_Three), 1.40
(3H, s, CH_Three), 1.43 (3H, s, CH_Three), 1.50 (3H, s, C
H_Three), 3.90-4.30 (5H, m, CH_Two, CH), 4.75 (1H, d, CHC
N). Infrared absorption spectrum (KBr, ν_max(cm^-1)) 3400,
 1380, 1370, 840. The recrystallized mother liquor was subjected to silica gel column chromatography.
After the first fraction, a further 3,4: 5,6-di-
0.51 g of O-isopropylidene-D-glucononitrile
I got Therefore, the total yield was 1.06 g (41.2% yield).
It was. From the second fraction, 3,4: 5,6-di-O-iso-
0.64 g (24.9) of propylidene-D-mannononitrile
%) As a colorless syrup. [0034] ¹H-NMR (CDCl_Three, δ) 1.37 (3H, s, CH_Three), 1.44
(6H, s, CH_Three), 1.50 (3H, s, CH_Three), 3.10 (1H, b, OH),
3.70-4.30 (5H, m, CH_Two, CH), 4.60 (1H, d, CHCN). Infrared absorption spectrum (film, ν_max(cm^-1)) 3400, 1
380, 1370, 840. Embodiment 2 5m Sodium cyanide adjusted to pH 9.0 with 3N hydrochloric acid
g of water (100 μL) solution was added to 2M sodium carbonate-hydrochloric acid.
400 μL of a buffer solution (pH 10.9) was added thereto.
5-di-O-isopropylidene-D-arabinose 23
mg of toluene (500 μL), and the mixture was added at room temperature for 20 minutes.
Stirred for minutes. The obtained reaction mixture was adjusted to pH 4.0 with 3N hydrochloric acid.
And the toluene layer was separated. This is a high-speed liquid
Matographie (Radial Pack 5C18, 0.8 × 10
cm, acetonitrile-0.003 M potassium dihydrogen phosphate
(1: 1), 1.0 mL / min, differential refractive index detector)
And then subjected to 3,4: 5,6-di-O-isopropylpropionate treatment.
15.5 mg (60.3%) of Riden-D-glucononitrile
And 3,4: 5,6-di-O-isopropylidene-D-manno
6.0 mg (23.3%) of nonitrile were obtained. Embodiment 3¹³ 130 mg of potassium C-cyanide and 2,3: 4,5-di-
460 mg of O-isopropylidene-D-arabinose
The reaction was carried out in the same manner as in Example 2, and the product was
Separation by chromatography, from ether / hexane
Recrystallize to give 3,4: 5,6-di-O-isopropylidene-D
-[1-¹³C] -Glucononitrile 230 mg (44.7
%) As colorless needle crystals. Melting point: 81.2-82.4 ° C¹³ C-NMR (CDCl_Three, δ) 117.9 (¹³CN) Embodiment 4 2,3,4,5-tetra-O-benzyl-D-arabinose 1
2M solution in 02 mg of tetrahydrofuran (2 mL)
0.2 mL of potassium anion solution, 0.2 mL of 1N hydrochloric acid and 1
1.6 mL of M sodium carbonate-hydrochloric acid buffer (pH 10.9)
Was added and stirred at room temperature for 1 hour. The obtained reaction solution is
And extracted with ethyl acetate. Wash this extract with water,
After drying and removing the solvent under reduced pressure, the residue
Recrystallized from 3,4,5,6-tetra-O-beige as colorless needles.
45 mg of benzyl-D-mannononitrile were obtained. Melting point 83-84 ° C. ¹H-NMR (CDCl_Three, δ) 3.39-4.18 (5H, OCH, OC
H_Two), 4.33-4.85 (9H, CNCH, OCH_Two-phenyl), 7.00-7.50
(20H, aromatic H). Infrared absorption spectrum (Nujol, ν_max(cm^-1)) 3400, 109
0, 1040, 1020, 1000, 740, 690. Reference Example 1 3,4: 5,6-di-O-isopropylidene-D-hexononi
Dissolve 1.24 g of tolyl in 10 mL of acetonitrile,
To this, 0.96 mL of triethylamine was further added. 0 ° C
While stirring with methane, add 0.5 ml of methanesulfonyl chloride
After adding mL, the mixture was stirred for 2 hours while returning to room temperature. Next
Then, pour the reaction mixture into ice water and extract with ethyl acetate.
Issued. After washing this extract with water, anhydrous magnesium sulfate
Dried on a plate. After distilling off the solvent under reduced pressure, the residue
The target fraction obtained was subjected to gel chromatography.
Concentrate to dryness under reduced pressure, and re-evaporate the residue from ether / hexane.
Crystallize to give 3,4: 5,6-di-O-isopropylidene-2-
O-methanesulfonyl-D-hexononitrile 1.23 g
(76.1%) were obtained as white needles. Melting point 82-92 ° C. ¹H-NMR (CDCl_Three, δ) 1.33 (3H, s, CH_Three), 1.43
(6H, s, CH_Three), 1.50 (3H, s, CH_Three), 3.23 (3H, s, SO_TwoCH
_Three), 3.70-4.40 (5H, m, CH_Two, CH), 5.45, 5.51 (1H, d,
 J = 3Hz, CHCN). Infrared absorption spectrum (nujol, ν_max(cm^-1)) 1380, 137
5, 1180. Reference Example 2 2,3: 4,5-di-O-isopropylidene-D-arabinose
Was dissolved in 30 mL of toluene, and sulfuric acid was added to the solution.
0.51 g of tetrabutylammonium hydrogen oxy, 1N hydroxylation
Sodium aqueous solution 22 mL, p-bromobenzenes chloride
2.30 g of rufonyl and 0.60 g of potassium cyanide in water
(5 mL) solution was added sequentially and vigorously stirred at room temperature for 8 minutes.
Stirred. Thereafter, in the same manner as in Reference Example 1, 2-O-
(P-bromobenzenesulfonyl) -3,4: 5,6-di-O
2.82 g of isopropylidene-D-hexonitrile (7
8.8%) as white powder crystals. Melting point 39-41 ° C ¹H-NMR (CDCl_Three, δ) 1.35 (3H, s, CH_Three), 1.40
(6H, s, CH_Three), 1.45 (3H, s, CH_Three), 3.70-4.30 (5H, m,
CH_Two, CH), 5.33, 5.42 (1H, d, J = 3Hz, CHCN), 7.80 (4
(H, d, J = 3Hz, Ph-H). Infrared absorption spectrum (neat, ν_max(cm^-1)) 1570, 139
0, 1380, 1190. Reference Example 3 3,4: 5,6-di-O-isopropylidene-D-hexononi
Dissolve 514 mg of tolyl in 5 mL of tetrahydrofuran
Then, 0.4 mL of triethylamine was further added thereto. 0
While stirring at a temperature of ° C, p-toluene chloride was added to the above solution.
500 mg of sulfonyl in tetrahydrofuran (1 mL)
After adding the solution, the mixture was stirred for 1.5 hours while returning to room temperature. Thereafter, in the same manner as in Reference Example 1, 3,4: 5,6-
Di-O-isopropylidene-2-O- (p-toluenes
602 mg (73.2 of ruphonyl) -D-hexononitrile.
%) As white floc. Melting point 77-78 ° C ¹H-NMR (CDCl_Three, δ) 1.33 (3H, s, CH_Three), 1.40
(6H, s, CH_Three), 1.43 (3H, s, CH_Three), 2.47 (3H, s, CH_Three),
 3.70-4.30 (5H, m, CH_Two, CH), 5.27, 5.40 (1H, d, J =
3Hz, CHCN), 7.40, 7.87 (each 2H, d, J = 9Hz, Ph-H). Infrared absorption spectrum (nujol, ν_max(cm^-1)) 1590, 118
0, 850. Reference Example 4 2,3: 4,5-di-O-isopropylidene-D-arabinose
1.15 g was dissolved in 30 mL of toluene.
0.35 g of hydrogen tetrabutylammonium, 1N hydroxide
15 mL of thorium aqueous solution, p-toluenesulfonyl chloride
Dissolve 1.6 g and 0.40 g of potassium cyanide in water (5 mL)
The liquids were added sequentially and stirred vigorously at room temperature for 8 minutes. Thereafter, in the same manner as in Reference Example 2, 3,4: 5,6
-Di-O-isopropylidene-2-O- (p-toluene
1.81 g (88.1) of sulfonyl) -D-hexonitrile
%) As white powder crystals. Reference Example 5 3,4: 5,6-di-O-isopropylidene-D-hexononi
Dissolve 1.09 g of tolyl in 1 mL of dimethyl sulfoxide
0.76 mL of carbon disulfide and 4N at a temperature of 0 ° C.
Add 1.06 mL of aqueous sodium hydroxide solution and stir for 15 minutes.
After stirring, add 0.260 mL of methyl iodide and pull further.
Subsequently, the mixture was stirred for 30 minutes. Thereafter, in the same manner as in Reference Example 1, 3,4: 5,6-
Di-O-isopropylidene-2-O-[(methylthio)
Thiocarbonyl] -D-hexononitrile 580 mg
(39.4%) as a yellow syrup. [0054] ¹H-NMR (CDCl_Three, δ) 1.33 (3H, s, CH_Three), 1.45
(3H, s, CH_Three), 1.52 (3H, s, CH_Three), 1.55 (3H, s, CH_Three),
 2.62 (3H, s, CH_Three), 3.80-4.50 (5H, m, CH_Two, CH), 6.
21, 6.37 (1H, each d, J = 3 Hz, CHCN). Infrared absorption spectrum (neat, ν_max(cm^-1)) 1380, 137
0, 840. Reference Example 6 2,3: 4,5-di-O-isopropylidene-D-arabinose
Was dissolved in 0.4 mL of benzene, and sulfuric acid was added to the solution.
Hydrogen tetrabutylammonium 34mg, 0.5N hydroxylation
0.4 mL of aqueous sodium solution, 50 μL of carbon disulfide, iodine
50 μL of methyl cyanide and 5.2 mg of potassium cyanide in succession
, And reacted in the same manner as in Reference Example 2 to give 3,4: 5,6-
Di-O-isopropylidene-2-O-[(methylthio)
Thiocarbonyl] -D-hexononitrile 26.0 mg
(75.0%). Reference Example 7 3,4: 5,6-di-O-isopropylidene-2-O-[(me
Tylthio) thiocarbonyl] -D-hexononitrile 7
0 mg was dissolved in 0.4 mL of benzene.
0.1 mL of Libutyltin and α, α'-azobisisobutyro
4 mg of nitrile was added, and the mixture was placed on an oil bath at a temperature of 100 ° C. for 30 minutes.
Stirred for minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain a residue.
To silica gel chromatography to reduce the target fraction
Concentrate to dryness under pressure and leave in the freezer to remove crystalline 2-de
Oxy-3,4: 5,6-di-O-isopropylidene-D-g
44 mg (90.5%) of lucononitrile were obtained. Melting point: 25 ° C. ¹H-NMR (CDCl_Three, δ) 1.35 (3H, s, CH_Three), 1.40
(3H, s, CH_Three), 1.45 (3H, s, CH_Three), 1.47 (3H, s, CH_Three),
 2.78 (2H, m, CH_TwoCN), 3.60-4.20 (5H, m, CH_Two, CH). Infrared absorption spectrum (neat, ν_max(cm^-1)) 2250, 138
5, 1375, 840. Reference Example 8 2,3: 4,5-di-O-isopropylidene-D-arabinose
230 mg of methanol in 0.5 mL of methanol.
While stirring at temperature, add 70 mg of potassium cyanide
Water (0.5 mL) solution, carbon disulfide 0.5 mL,
0.5 mL of chill and 0.5 mL of dimethyl sulfoxide are successively added.
And stirred for 20 minutes while returning to room temperature. The obtained reaction mixture was poured into ice water.
After that, it was extracted with dichloromethane and the organic layer was separated.
Then, the solvent was distilled off under reduced pressure. The obtained residue is benzene
Dissolve in 2 mL, 0.5 mL of tributyltin hydride and
α, α'-azobisisobutyronitrile 20 mg was added,
The mixture was stirred at a temperature of 100 ° C. for 10 minutes on an oil bath. After this,
In the same manner as in Reference Example 7, 2-deoxy-3,4: 5,6-di-
O-isopropylidene-D-glucononitrile 185m
g (76.8%). Reference Example 9 3,4: 5,6-di-O-isopropylidene-2-O- (p-
Toluenesulfonyl) -D-hexononitrile 300 m
3 g of a 30% acetic acid aqueous solution was added to the mixture, and the mixture was heated to 110 ° C.
For 5 minutes. Thereafter, the solvent is distilled off under reduced pressure.
The residue was extracted with ethyl acetate and water.
Was. The organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate.
And dried. Then, the solvent is distilled off under reduced pressure, and the residue is
Reduce the target fraction under reduced pressure by Ricagel chromatography
It was concentrated to dryness underneath to give 3,4-O-isopropylidene-2-
O- (p-toluenesulfonyl) -D-hexononitrile
270 mg (100%) were obtained. [0062] ¹H-NMR (CDCl_Three, δ) 1.43 (3H, s, CH_Three), 1.47
(3H, s, CH_Three), 2.48 (3H, s, Ph-CH_Three), 3.5-4.5 (5H,
m, CH_Two, CH), 5.45, 5.55 (1H, each d, J = 3Hz, CHCN),
 7.40, 7.88 (each 2H, d, J = 9HZ, Ph-H). Infrared absorption spectrum (neat, ν_max(cm^-1)) 3500, 159
0, 1380, 1190, 1175. Reference Example 10 3,4: 5,6-di-O-isopropylidene-2-O- (p-
Toluenesulfonyl) -D-hexononitrile 123m
g in 1 mL of ethanol, 2 mL of water and
Strongly acidic ion exchange resin "Dowetux" 50WX8 (H
⁺) Add 0.5 g and put on oil bath at 110 ° C for 15 minutes
While stirring. Next, the ion-exchange resin is filtered off during warming.
The filtrate was cooled to 0 ° C., and the precipitated crystals were collected by filtration.
-O- (p-toluenesulfonyl) -D-hexononite
14 mg (14.1%) of ril were obtained. Melting point 161-163 ° C (decomposition) Infrared absorption spectrum (nujol, ν_max(cm^-1)) 3300, 159
0, 1370, 1190, 1180. Reference Example 11 3,4: 5,6-di-O-isopropylidene-2-O- (p-
Toluenesulfonyl) -D-hexononitrile 25 mg
Was suspended in 1 mL of a 30% aqueous acetic acid solution, and
Heated at a temperature of 5 ° C for 5 minutes, then
Add 50 mg (50%) and stir on oil bath for 10 minutes
Was. After the completion of the reaction, the catalyst was separated by filtration, and the filtrate was separated by Sepha.
Attached to column chromatography of Decks LH-20
And eluted with water. The target fraction is ion-exchange resin "Dow
ETCSU 50WX8 (H⁺) "And AG1X8 (HCO_Three
^-) To give 2-deoxy-D-glucose 6.0m
g (61.0%) were obtained. This product is intended for use in high-performance liquid chromatography
IODEX S801, 8mm x 50cm, 1.1mL water
/ Min, 72 ° C., differential refractive index detector), Rt = 1
Indicate 1.2 minutes, and use thin layer chromatography (Merck
・ Pre-coated plate, silica gel 60F254, Ase
Tonitrile / water (9/1 (v / v), 15% alcohol
Sprayed with sulfuric acid, detected at 150 ° C), Rf = 0.3
1, which is consistent with the standard 2-deoxy-D-glucose
did. Reference Example 12 2-O- (p-bromobenzenesulfonyl) -3,4: 5,6
-Di-O-isopropylidene-D-hexononitrile 2
8 mg was treated in the same manner as in Reference Example 11 to give 2-deoxy-
4.9 mg (50.0%) of D-glucose were obtained. This product also
High-performance liquid chromatography was performed in the same manner as in Reference Example 11.
And thin-layer chromatography matched the standard. Reference Example 13 3,4: 5,6-di-O-isopropylidene-2-O- (p-
(Toluenesulfonyl) -D-hexononitrile 411m
g was treated in the same manner as in Reference Example 11 and then recrystallized from acetone.
Crystallize to give 48 mg of 2-deoxy-D-glucose as white
Obtained as powder crystals. This product is also similar to Reference Example 11.
High-performance liquid chromatography and thin-layer chromatography
It coincided with the standard on FE. In addition, melting point and infrared absorption
The spectrum was also consistent with the standard. [0070] Infrared absorption spectrum (nujol, ν_max(cm^-1)) 3400-3100 Reference Example 14 4.2mg of potassium cyanide and tetrabutylan hydrogen sulfate
6 mg of monium in 0.4 N aqueous solution of sodium hydroxide 0.4 m
L, and add 2,3: 4,5-di-O-isopropyl
27 mg of den-D-arabinose and p-toluene chloride
A solution of 15 mg of rufonyl in benzene (0.4 mL) was added,
Stir vigorously at room temperature for 10 minutes. Next,
A solution of 38 mg of ruenesulfonic acid in water (0.1 mL) and 60
% Acetic acid aqueous solution (0.4 mL), and heated to 110 ° C on an oil bath.
The mixture was stirred for 10 minutes while the solvent was distilled off. Thereafter, 1 mL of benzene and saturated hydrogencarbonate were added.
Neutralize by adding 3 mL of thorium aqueous solution, and separate the organic layer.
The solvent was then distilled off under reduced pressure. To the obtained residue
Add 1 mL of 30% acetic acid aqueous solution and 100 mg of Raney alloy
And stirred at 110 ° C. for 10 minutes on an oil bath. Next, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure.
After drying to dryness, first, ion exchange resin "Dowetux"
50WX8 (H⁺), Then "Dowetux" A
G1X8 (HCO_Three ^-) To give 2-deoxy-D-
5.0 mg (48%) of glucose were obtained. This product is also a reference example
High-performance liquid chromatography and thin
It was in agreement with the standard by layer chromatography. Reference Example 15 4.0 mg of potassium cyanide and tetrabutylan hydrogen sulfate
6 mg of monium in 0.4 N aqueous solution of sodium hydroxide 0.4 m
L, and add 2,3: 4,5-di-O-isopropyl
27 mg of den-D-arabinose and p-bromoben chloride
A solution of 20 mg of zensulfonyl in benzene (0.4 mL) was added.
In addition, the mixture was vigorously stirred at room temperature for 10 minutes. Thereafter, processing is performed in the same manner as in Reference Example 14.
And 4.4 mg of 2-deoxy-D-glucose (45.0
%). This product was prepared in the same manner as in Reference Example 11
By body chromatography and thin layer chromatography
It matched the standard. Reference Example 16 256 mg of D-arabinose diethyldithioacetal
Hydride in dimethylformamide (3 mL) solution
300 mg suspension (60% suspension) and add
Stirred for hours. 1.02 g of benzyl bromide was added thereto under ice cooling.
The mixture was stirred overnight at room temperature. After this, dilute the reaction solution with water
And extracted with ethyl acetate. Wash the extract with water and dry
After that, the solvent was removed under reduced pressure. The resulting residue is
2,3,4, colorless oil
5-tetra-O-benzyl-D-arabinose diethyl
500 mg of dithioacetal was obtained. [0077] ¹H-NMR (CDCl_Three, δ) 1.10 (3H, CH_Three), 1.17 (3
H, CH_Three), 2.48 (2H, SCH_Two), 2.65 (2H, SCH_Two), 3.50-4.
40 (6H, OCH_Two, OCH), 4.40-5.00 (8H, OCH_Two-phenyl), 7.
05-7.50 (20H, aromatic H). Reference Example 17 2,3,4,5-tetra-O-benzyl-D-arabinose di
250 mg of ethyldithioacetal acetone (2.5 m
L) and water (0.2 mL) in a solution of mercuric chloride 220m
g and mercuric oxide (220 mg) for 2 hours at room temperature
Stirred. The insoluble material is filtered, and the obtained filtrate is concentrated under reduced pressure.
Shrunk. The obtained residue is dissolved in chloroform, and
Wash with aqueous potassium iodide and saturated saline, dry
Was. Then, the solvent is distilled off under reduced pressure, and the obtained residue is
Recrystallized from xane to give colorless granular 2,3,4,5-tetra
100 mg of -O-benzyl-D-arabinose was obtained. Melting point 61-62 ° C. Reference Example 18 3,4,5,6-tetra-O-benzyl-D-mannononitrile
To a solution of 110 mg of acetonitrile (3 mL)
20 mg of tylamine and p-toluenesulfonyl chloride 38
mg was added and stirred at room temperature for 4 hours. The solvent was distilled off
Then, water and ethyl acetate were added to the residue, and the organic layer was separated.
Was. The organic layer was washed with water, dried, and then dried under reduced pressure.
And the resulting residue is purified by silica gel chromatography.
And eluted with hexane-ethyl acetate (5: 1)
3,4,5,6-tetra-O-benzyl-2-Op-
105 mg of ruensulfonyl-D-aldononitrile
Obtained as a colorless syrup. [0082] ¹H-NMR (CDCl_Three, δ) 2.40 (3H, CH_Three), 3.45-4.2
0 (5H, OCH_Two, OCH), 4.25-4.90 (8H, OCH_Two-phenyl), 5.
20 (CNCH), 5.39 (CNCH), 7.10-7.80 (24H, aromatic
H).

Claims (1)

(57) [the claims] 1. General formula (Wherein ^* C represents ¹¹ C, ¹³ C or ¹⁴ C, and OR ¹ , OR ² ,
OR ³ and OR ^{4 each} represent a protected hydroxyl group, and X represents an alkanesulfonyl group, an arenesulfonyl group or an alkylthiothiocarbonyl group. An aldononitrile derivative represented by the formula: