JPH01139591A - Wholly automatic device for synthesizing 11c-labeled glucose - Google Patents

Abstract

PURPOSE:To obtain a device capable of wholly automatically synthesizing the title compound for research of saccharometabolism, etc., in high yield and selectivity in a short time, by reacting an alkaline aqueous solution with a <11>C-labeled HCN and specific arabinose derivative in a reaction vessel, reducing the resultant product, hydrolyzing the reduction product and purifying the formed hydrolyzate by treatment using a column. CONSTITUTION:An alkaline aqueous solution is added to a reaction vessel 11 and <11>C-labeled hydrogen cyanide 1 and 2,3:4,6-di-O-isopropylidene-D-arabinose solution 2 are injected thereinto and reacted to form 3,4:5,6-di-O-isopropylidene-D- glucononitrile. Raney nickel or Raney alloy catalyst from a catalyst vessel 10, together with an aqueous solution 3 of an acid, is then fed to the reaction vessel 11 to reduce and simultaneously hydrolyze the resultant product. The obtained reaction solution is subsequently passed through ion exchange resin columns 14 and 15, concentrated in a concentrating vessel 16, passed through a high-speed liquid chromatography column 24 and purified to recover the product in a vial 28. Thereby the aimed compound is wholly automatically synthesized.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an apparatus for automatically synthesizing isotope-labeled D-glucose in which the carbon atom at position 1 is labeled with l l CT:.

D-glucose labeled with 11C at the 1st carbon position is useful for in vivo sugar metabolism research and clinical diagnosis. For example, it is essential for positron emission tomography, and is used for diagnosis of cerebral circulation disorders, mental disorders, myocardial infarction, early detection of malignant tumors, etc.

However, IC is a radionuclide and 2
Because it has a short half-life on the order of 0 minutes, it is essential that lICD-glucose be synthesized extremely quickly while preventing radioactive contamination.

In order to meet such demands, for example,
Publication No. 64995 discloses that D by causing plant leaf discs to carry out photosynthesis using carbon dioxide labeled with 11C.
- A device for automatically producing glucose has been proposed.

However, when using this method, the labeling position of the obtained D-glucose is not clear, and furthermore, it requires separation from plant components, making the operation complicated, and especially when used for clinical diagnosis. Since it is necessary to remove pyrogens and other physiologically active substances in advance,
This method is not practical as a method for producing JD-glucose.

On the other hand, in general, the typical method for producing isotope-labeled glucose is to react D-arabinose with an isotope-labeled cyanide compound to produce a cyanohydrin derivative, which is then reduced and hydrolyzed. Are known. However, when this method is used, the obtained cyanohydrin derivative is a mixture containing mainly mannose coordination, and it is extremely difficult to separate the glucose coordination cyanohydrin derivative from the mixture. Furthermore, loss of the labeling precursor also occurs, so the desired D-
Glucose cannot be obtained in high yield.

Furthermore, a method is also known in which D-arabinose is reacted with an isotope-labeled cyanide compound to obtain a cyanohydrin derivative, which is hydrolyzed to lead to gluconic acid, which is then lactonized and then reduced. However, since this method requires a long reaction time and complicated operations, it cannot be applied to the production of D-glucose using 11C, which is an isotope with a short half-life. Moreover, the yield of D-glucose from this reaction is also low.

The present invention is based on the D-
This was developed to solve the above-mentioned problems in the production of glucose, and the 1-position carbon can be produced in a simple operation, in a short time, with high yield, and with high selectivity, using a 11C-labeled cyanide as a 10 isotope source. An object of the present invention is to provide an automatic synthesis device for isotope-labeled D-glucose that can produce IC-labeled D-glucose.

The automatic glucose synthesis device according to the present invention can be used to synthesize IC-labeled hydrogen cyanide, acid aqueous solution, alkaline aqueous solution, 2.3F
4.5-di-0-isopropylidene-D-arabino-°
a reaction vessel connected to respective supply means for a gas solution and a Raney nickel catalyst or a Raney alloy; an ion exchange resin column connected to the reaction vessel; and a concentration vessel connected to the ion exchange resin column; It is equipped with a high performance liquid chromatography column connected to this concentration container and a glucose collection container connected to this. First, an aqueous alkali solution, 11C labeled hydrogen cyanide and 2.3:4.5- Inject the di-0-isopropylidene-D-arabinose solution to increase the reaction volume WG.
within 3.4:5.6-di-0-isopropylidene-D-
A solution containing glucononitrile is generated, and then Raney nickel or Raney alloy catalyst is injected into a reaction vessel together with an acid aqueous solution, and 3,4:5.6-di-O-isopropylidene-D-glucononitrile is produced in the reaction vessel. The nitrile is reduced and simultaneously hydrolyzed to produce a solution containing ICD-glucose, and then this aqueous solution is transferred through an ion exchange resin column to a concentration vessel, where the aqueous solution is concentrated, and then the obtained It is characterized in that the concentrated liquid is transferred to a high performance liquid 20 magnetic column and the obtained 1ICD-glucose is collected.

First, the 11c isotope label D in the device according to the invention
- Describe the glucose production process.

In the apparatus of the present invention, first, 2,3:4.5-di-0-isopropylidene-〇-7 ravinose represented by the formula % formula % () (wherein R is a hydrogen atom or an alkali 3,4F5.6-di-0-isopropylidene-D-glucononitrile represented by the general formula is produced by reacting the 11c isotope-labeled cyanide represented by is reduced and simultaneously hydrolyzed in the presence of a catalyst to produce 11CD-glucose represented by the general formula %.

In the apparatus of the present invention, as a first step, 2,3:4゜5-di-
By reacting O-isopropylidene-D-arabinose with the 11C isotope-labeled cyanide compound represented by the general formula (n) and condensing it, the compound of the general formula (11
Isotopic label 3,4:5.6-di-0 represented by [)
-Isopropylidene-D-glucononitrile (hereinafter sometimes referred to as aldononitrile aff 5 body) is obtained.

Here, as the alkali metal in the cyanide compound represented by the general formula (11), for example, lithium, sodium, or potassium is suitable.

The above condensation reaction is usually carried out using a dilute alkaline aqueous solution, such as a sodium bicarbonate aqueous solution, which is a solvent for dissolving the cyanide compound, and 2,3:4,5-di-0-isopropylidene-D-arabinose. 8. Usually in a mixed solvent with an appropriate aqueous solvent such as methanol, ethanol, methyl cellosolve, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethylformamide, benzene, toluene, xylene, cumene, etc. It is carried out at a temperature of 0 to 50°C. In particular, in the present invention, in order to increase the reaction rate,
1 to 1 in the high pH region, preferably 8.0 to 10.0
It is preferable to react for 0 minutes.

According to the above reaction, in addition to the aldononitrile derivative represented by the general formula (I[I), its isomer is also produced as a by-product. However, one advantage of the above-described method is that it is possible to obtain reaction products that are predominantly glucose-coordinated aldononitrile derivatives. Furthermore, according to the above method, by using a water-incompatible solvent as the organic solvent, the formation of the above isomer is suppressed, and the glucose-coordinated aldononitrile derivative is more selectively produced. It can be obtained by sex.

In the present invention, the above 3, 4: 5, 6. , the mixture of isomers of di-O-isopropylidene-D-glucononitrile is directly subjected to the second step of reduction and hydrolysis, reducing the cyano group and hydrolyzing the isopropylidene group at the same time. D-glucose with a labeled carbon atom is obtained.

In the present invention, reduction and hydrolysis are carried out by adding Raney nickel or Raney alloy and an aqueous acid solution such as formic acid, acetic acid, hydrochloric acid, or sulfuric acid into the reaction vessel after the cyanohydrin synthesis.

The reaction solution containing the isotope D-glucose thus obtained can be passed through an ion exchange resin column to remove the acid and byproducts used in the reduction and hydrolysis reactions. It is then transferred to a high performance liquid chromatography column where it is separated and collected.

EMBODIMENT OF THE INVENTION Below, based on the drawing which shows an Example, the apparatus and its operation|movement for each process by this invention are demonstrated in detail.

(1) Degassing process Open the solenoid valve VZ'l, connect the high performance liquid chromatography eluent 29 to the vacuum line V, and at the same time connect the stirrer 3
Activate α to degas the eluent.

On the other hand, the column heater 25 is activated and a normal rotation signal is input to the high-pressure six-way valve 22.

(2) Synthesis Preparation Step Open the solenoid valve v4 to open the exhaust port of the reaction vessel 11, close the valve (2), and fill the catalyst vessel 10 with 100 μl of a 20% imidazole aqueous solution and 30 μL of Raney nickel.

Next, 23 μm of 2,3:4°5-di-0-isopropylidene-D-arabinose in toluene (500
At the same time as adding the μl solution, formic acid-4N hydrochloric acid (
Add 1:1) 400μ2, and then add 50μ2 of water to the injection port 36.
After adding 0μ2, heater 17 for concentration vessel 16
Activate. Next, in the reaction vessel 11, 400 ml of 1M sodium carbonate-hydrochloric acid (pH 0.8) and 2.5 ml of sodium cyanide adjusted to pH 9.0 with 3N hydrochloric acid were added.
Add 50 μl of an aqueous solution of

With this, preparations for synthesis are completed, and a 1C-labeled hydrogen cyanide production apparatus (not shown) connected to a cyclotron is started to produce IC-labeled hydrogen cyanide.

(3) Synthesis step Open the solenoid valve ■, operate the stirrer 13, introduce H''CN together with nitrogen gas into the reaction vessel 11, simultaneously open ■, supply water to the water meter 6, By sensing the water surface with the optical sensor 8, close the
Weigh. After that, close (1), open V2 and V6, and pour the toluene solution of 2.3:4.5-di-0-isopropylidene-D-arabinose in the inlet 2 into the reaction vessel 1.
1. Next, the electromagnetic valve (6) is closed and the stirring in the reaction vessel 11 is continued to complete the cyanohydrin synthesis and 3,4:5,6-di-0-isopropylidene-D-
Glucononitrile is produced in the reaction vessel 11.

Next, input is input to the heater 12, solenoid valve 2 is closed, and solenoid valves 2 and V are opened, and the Raney nickel in the catalyst container IO is injected into the reaction container 11 together with the formic acid-hydrochloric acid aqueous solution in the injection port 3. Then, close solenoid valve ■7. As a result, 3,4:5,6-di-
O-isopropylidene-D-glucononitrile is reduced and simultaneously hydrolyzed to produce the isotope D-glucose.

Next, close the solenoid valve 4, close the exhaust port of the reaction vessel 11, open the solenoid valve V (and open the solenoid valve V22,
1 ml of water in the water meter 6 is introduced into the reaction vessel 11, then the heater 12 is turned off, the stirrer 13 is turned off, the stirrer 18 is activated, and the solenoid valves V3, V? ,Vll
, VI4, VI5, VI9, and VZG are opened, and the aqueous solution in the reaction vessel 11 containing the reaction product is transferred to the concentration vessel 16 via the ion exchange resin columns 14 and 15 by nitrogen gas pressure.

Here, the ion exchange resin column 14 is filled with, for example, [Amberlite CG-120 (11ゝ)], and the ion exchange resin column 15 is filled with, for example, [Amberlite CG-120 (11ゝ)].
It is filled with Amberlite 8G1-X8 (llcO3-) J. Therefore, the ion exchange resin column 14 removes basic byproducts from the reaction solution, and the ion exchange resin column 15 removes formic acid, hydrochloric acid, and acidic byproducts used in the hydrolysis reaction from the reaction solution. This is a pretreatment for subsequent separation and purification by high performance liquid chromatography.

At the same time as described above, the solenoid valve (2) is opened, water is poured into the water meters 6 and 7, and the optical sensor 9 is made to sense the water surface, so that the valve (2) is closed and 8 ml of water is measured.

Next, open the solenoid valve V4 at the exhaust port of the reaction vessel 11, open the solenoid valves V and v2□, inject water 8i1 into the reaction vessel 11 under reduced pressure using the vacuum line ■, and start the stirrer 13. to stir the inside of the reaction vessel 11, then turn off the stirrer I3, and turn off the solenoid valves V a , V b and
2 Close □, open ■, and fill the reaction vessel 11 with nitrogen gas.
The water inside is transferred to the concentration container 16.

Next, the solenoid valve 2 is opened to reduce the pressure in the concentration container 16, and concentration is started while heating and stirring. Close solenoid valve ■3 and close V7 to stop the supply of nitrogen gas, and at the same time, solenoid valve v! , V4 and V6 to open the inside of the reaction vessel 11 to atmospheric pressure. Thereafter, the t-magnetic valve V4 at the exhaust port of the reaction container 11 is closed to reduce the pressure inside the reaction container 11, and stirring is carried out while introducing air from the injection port 2. After this, solenoid valve V2
and (1) 6 are closed, V and V are opened, and the water in the reaction vessel 11 is transferred to the concentration vessel 16 again by nitrogen gas pressure.

After the transfer to the concentration container 16 is completed, the solenoid valve v*
, V, , V13, VB2, V+S, and Vll are closed, and the aqueous solution containing the isotope D-glucose, which is a reaction product, in the concentration container 16 is concentrated under reduced pressure.

By collecting the effluent from this concentration process in an ice-cooled trap 19 and sensing the liquid level with a liquid level gauge 20,
Complete concentration.

Therefore, the heater 17 of the concentration container 16 is turned off, and the solenoid valve V
l? Then, open VB9 and inject 0.5 ml of water from the inlet 36 into the concentration container 16. Next, the solenoid valve V17 is opened and closed to introduce air and dissolve the concentrate adhering to the wall of the concentration container 16, and then the solenoid valve 2° is closed to reduce the pressure inside the concentration container 16. unlock.

After this, the solenoid valve V17 is closed, V16 and Vll are opened, and the syringe pump 27 is driven to remove the air in the loop of the high-pressure six-way valve 22, and then the agitator 18
, the high pressure six-way valve 22 is reversed, the loop is connected to the concentration container 16, the syringe pump 27 is reversed,
The concentrated liquid in the concentration container 16 is drawn into the loop of the high pressure six-way valve 22. Here, the liquid in the pipe is interrupted and the concentration container 16
When the inside is empty, this is sensed by the optical sensor 21, thereby operating a motor (not shown) that drives the high-pressure six-way valve 22, and connecting the loop to the high-performance liquid chromatography column 24. The concentrate in the loop is thus injected into the high performance liquid chromatography column 24. The high-performance liquid chromatography eluent 29 passes through the electromagnetic valve 6 and is delivered to the high-performance liquid chromatography pump 23.
The water is connected to the pump and transferred to the high-pressure six-way valve 22 by this pump.

At the same time, the solenoid valve V34 is opened to release the reduced pressure of the syringe pump suction. When the refractive index detector 26 of the high performance liquid chromatography detects the peak of glucose, the electromagnetic valve 2□ is opened to collect the target isotope D-glucose in the vial 28. When collection is completed, solenoid valve V21 is closed and the synthesis process is completed.

(4) Washing the reaction vessel, regenerating the column, and drying these steps The stirrer 13 and heater 12 are operated, and the solenoid valve V3,
V4, ■, and Vll are opened to inject hydrochloric acid from the hydrochloric acid reservoir 31 into the reaction vessel 11. The solenoid valve Vll and the column heater 25 are energized in preparation for the next synthesis.

After closing solenoid valves V6 and Vll, heating and stirring to dissolve the Raney nickel in reaction vessel 11, solenoid valve
is closed, V7 and V13 are opened, and the hydrochloric acid in the reaction vessel 11 is discharged through the column 14.

Next, close the solenoid valve ①, open V4, V6 and Vll, add hydrochloric acid into the reaction vessel 11 again, stir it, and then
This hydrochloric acid is discharged and the ion exchange resin column is regenerated.

Next, the heater 12 is turned off, the solenoid valves (1) and (2) are opened 1°, and water is injected into the reaction vessel 11.

Solenoid valves v4 and V,. Close it, open vff2, and completely empty the inside of the pipe. Close solenoid valve V6 and viz, and
is opened, and the water in the reaction vessel 11 is discharged through the column 14 under nitrogen gas pressure. This operation is repeated an appropriate number of times, for example, three times, to wash the reaction container 11 and column 14 with water.

Next, the solenoid valve 6 and VlZ are opened, and the sodium hydrogen carbonate aqueous solution is injected under reduced pressure from the sodium hydrogen carbonate solution reservoir 32 into the reaction vessel 11, and at the same time, Vl6, V (
,,Open V 1 B and VB, and open the solenoid valve■.

is opened and the aqueous sodium hydrogen carbonate solution is discharged from the reaction vessel 11 to the waste liquid reservoir 35 through the ion exchange resin column 15 under nitrogen gas pressure. The sodium bicarbonate aqueous solution is again injected into the reaction vessel 11, the solenoid valve v4 at the exhaust port is opened, and the inside of the reaction vessel 11 is completely neutralized with alkali while sucking air. Open the solenoid valve ■2 inside the inlet,
Similarly, aspirate air to completely neutralize the acid in the inlet.

Next, close solenoid valves V2 and V6, open V3, and
The aqueous sodium hydrogen carbonate solution is transferred from the reaction vessel 11 to the waste liquid reservoir 35 via the column 15 at a nitrogen gas pressure of . By this operation, the ion exchange resin column 15 is regenerated.

After opening the solenoid valves V6 and Vl (l) and injecting water into the reaction vessel 11 under reduced pressure, close the solenoid valves v6 and
is opened and the water in the reaction vessel 11 is transferred to the waste liquid reservoir 35 through the column 15 under nitrogen gas pressure. This operation is repeated, for example, five times to wash the reaction vessel 11 and column 15 with water.

After this, solenoid valve V? , V's, VH2, VH2 and V
Close ZI1, ■6 and vl. Open to inject water into the reaction vessel 11, then open solenoid valves v6 and V3□, and proceed as follows.

The reactor was opened to apply nitrogen gas pressure, and the pressure reducing valve (2) was opened to transfer the water in the reaction vessel 1 to the concentration vessel I6. Here, the agitator 18 of the concentration container 16 is operated to wash the concentration container 16. Next, solenoid valves ■6 and ■2z
After opening and completely emptying water meters 6 and 7, close solenoid valves ■6 and ■2□, and open solenoid valve V.
The water in the reaction container 11 is transferred to the concentration container 16, and then
Close solenoid valves V7, Vllll and V2°, and close solenoid valve V17.
, Vl'l and VZa are opened to transfer the water in the concentration container 16 to the waste liquid reservoir 35.

Next, the solenoid valves V 3 , V 17 , Vl9 and Vl1
1 is closed and solenoid valves V, V2° and V31 are opened to draw water into the concentration vessel 16 through the loop of the high-pressure six-way valve 22 to clean the loop. Close solenoid valve V31 and turn V3
After opening V16 and VZG, the solenoid valves V17, V19, and V111 are opened to discharge the washing liquid in the concentration container 16 to the waste liquid reservoir 35. After this, solenoid valve V
, 7, close V 1 q, VZI and v34, and close the solenoid valve V
, (2) and (2) are opened, and water is poured from the distilled water reservoir 32 through the loop of the high-pressure six-way valve 22 into the condensation vessel 16 . Using the solenoid valve Vffl as exhaust, high pressure six-way valve 2
Completely empty the second loop.

Close the solenoid valve ■2゜, open Vl9, and
Return the inside of 6 to atmospheric pressure. Close the solenoid valve v, 4, close the exhaust port of the syringe pump, drive the syringe pump 27 4, and return the piston.

Next, the drive motor of the syringe pump 27 is reversed to suck the water in the concentration container 16 and fill the loop of the high-pressure six-way valve 22 with water, then close the solenoid valve V16 and close the solenoid valve V34 at the exhaust port. Open to return the syringe pump piston. Close the solenoid valve V34, turn Vl and ■. is opened, and the water in the concentration container 16 is discharged into the waste liquid reservoir 35.

Simultaneously with the return operation of the syringe pump, the solenoid valve V,
Then, VS2 is opened and methanol is injected into the reaction vessel 11 from the methanol reservoir 33. Next, the heater 12
input, open the solenoid valve ■4 of the exhaust port, and
The inside of the reaction vessel 11 is washed with methanol, and after this washing, the solenoid valves v4 and (1)6 are closed, and (2) and (2) are opened to discharge the methanol inside the reaction vessel 11 using nitrogen gas pressure. Next, the solenoid valve ■
, and open ■6 and ■3□ to completely suck the methanol in the pipe into the reaction vessel 11. After this, close the solenoid valves ■ and ■3□, open V7, exhaust methanol with nitrogen gas pressure, and connect the inlet loop of 2,3:4,5~Z-0-isopropylidene-D-arabinose. In addition to washing and drying, the reaction container 11 is also dried.

Next, close the solenoid valve ■2, turn off the heater 12, and turn off the solenoid valves V3 and Vl? , ■, and Vl11 are opened to completely remove the water remaining in the ion exchange column 15, the solenoid valves V 3 , V +, and Vl8 are closed, and (4) is opened to fill the reaction vessel 11 with nitrogen gas. Dry with.

At the same time, the solenoid valve VffS is opened to transfer the water in the trap 19 to the waste liquid reservoir 35 and dry the trap. After this solenoid valve V? , close VI9, VZ8 and V3%,
Complete cleaning, regeneration of the ion exchange resin column, and drying of the reaction vessel and trap in preparation for the next synthesis.

All operations of the above devices are controlled by a computer.

According to the apparatus of the present invention for producing whole fruits, as described above, 2,3:4.5-di-O-isopropylidene-D-arabinose is reacted with an isotope-labeled cyanide compound in a reaction vessel. Te, 3
, 4: 5,6-di-0-isopropylidene-D-glucononitrile is produced, and then reduced with a Raney nickel catalyst or Raney alloy catalyst in the same reaction vessel,
Since glucose whose 1-position carbon is labeled with the 11C isotope is produced by hydrolysis, the isotope D-glucose can be automatically produced in high yield.

An example of producing glucose by the method described above is given below as a reference example.

Reference example 1 Sodium cyanide 5 adjusted to pH 9.0 with 3N hydrochloric acid
Add the water (100μβ) solution of (2) to 2M sodium carbonate-hydrochloric acid buffer (pH 10.9) 400p 7! 2.3:4.5-di-0-isopropylidene-D-
Arabinose 23■ toluene (500 μl)? Solution U was added, and the mixture was stirred at room temperature for 20 minutes.

The resulting reaction mixture was adjusted to pl+4.0 with 3N hydrochloric acid, and the toluene layer was separated. This was subjected to high performance liquid chromatography (Radial Pack 5C18,0,8X IQcn
3,4:5,6-di-0
-isopropylidene-D-glucononitrile 15.5cm (60.3%) and 3,4:5,6-di-0-isopropylidene-D-mantunonitrile 6.0cm (23°3%)
) was obtained.

Melting point of Nosan and Kamijou: 82-84℃ Elemental analysis (as C+□+1.?NO5) C11
N Theoretical value 56.02 7.44 5.44 Actual value 55.95 7.48 5.35'H-NMR
(CDCl2.6) 1.37 (3H, s, CHz), 1.40 (31 (,
s, CH3), 1.43 (311, S, C1h)
, 1.50 (3H, S, C1h), 3.90-4
．． 30 (5tl, m, CH□, CH), 4.7
5 (IH, d, C11CN).

Infrared absorption spectrum (KBr, ν1Iax (C11-
')) 3400, 13B0.1370.840°3.4
:5,6-di-0-isopropylidene-D-mantunonitrile elemental analysis (as CIZHI9NO5) CHN Theoretical value 56.02 7.44 5.44 Actual value 55,84 7.49 5.39 JI N
M R (CDCI+, δ) 1.37 (3) 1. s,
CH:+), 1.44 (6B, s, CH3),
1.50 (3H, s, C113), 3.10 (11
(, b, 01l), 3.70-4.30 (5t
l, m, Hz, C)I), 4.60
(11I, d, C11CN).

Infrared absorption spectrum (film, v smx (Cm
-')) 3400, 1380.1370.840° Reference Example 2 3.4: 5,6-di-0-isopropylidene-D-glucononitrile 6■ in diisopropyl ether 500μl
It was dissolved in Raney nickel (wet weight 30
■) and 600 μl of 17% formic acid, and heated to 100℃ for 10 minutes.
Stir for a minute.

After the reaction, the catalyst was filtered off and the filtrate was subjected to chromatography using ion exchange resin Amberlite CG-120(H')J and then using [8G1-X8(HCOff-)J]. and glucose 2.4
Akebono (57.1%) was obtained.

This product is suitable for high performance liquid chromatography (Shodex 5801.8mm x 50cn+, water 1.1ml/min, 7
2°C, differential refractive index detector) showed Rt = 11.2 minutes,
It matched with the standard glucose.

In addition, the trimethylsilyl ether derivative obtained by heating at 60°C for 30 minutes using N,O-bis(trimethylsilyl)trifluoroacetamide and pyridine containing 1% trimethylchlorosilane was analyzed by gas chromatography (3% 0v- 17 treatment Chromosorp G Shizu-0MC
3 (80-100 meshes) 3.2 cranes x 1.6m, column temperature 190℃, inlet temperature 220℃, He, 50ml
/ minute) is 1? t = 13.4 minutes and 18.8 minutes, which coincided with the trimethylsilyl ether derivative obtained from standard glucose.

Reference example 3 pH of a 2.5-day aqueous solution of sodium cyanide with 3N hydrochloric acid
9.0, and 50μβ of this solution was added to 400μ of 1M sodium carbonate-hydrochloric acid buffer (pH 10.8). Add to this 500 μl of a toluene solution of 23 μl of 2.3:4.5-di-0-isopropylidene-D-arabinose.
was added and stirred at room temperature for 2 minutes.

Next, 20 mg of Raney nickel (wet weight 30 μ) and imidazole were suspended in 100 μ2 of water, this catalyst suspension was added to the above solution, and further, formic acid-4N hydrochloric acid (1:1
) 400 μl of the mixed solution was added and stirred at a temperature of 110° C. for 8 minutes.

After this, the catalyst was filtered off, and the filtrate was first treated with an ion exchange resin.
Amberlite CG-120()I'') J, then rAGl-X8 (HCO3-)J Wosoreso FL
Filling 1. After concentrating the eluent, high performance liquid chromatography (Shotex 3801, 8
Dragon x 50cm, water 1.1ml/min, differential refractive index detector)
Glucose 2.75mg (30.6%
) and 1.3 mg (14.4%) of mannose were obtained.

[Brief explanation of the drawing]

FIG. 1 is a diagram showing the configuration of an apparatus according to the present invention. 1...H"CN injection port, 2...2,3: 4.5-di-0-isopropylidene-D-arabinose injection port, 3
...Formic acid-hydrochloric acid aqueous solution inlet, 4...Nitrogen gas supply port, 5...Pressure regulator, 6 and 7...Water meter, 8
and 9... optical sensor, 10... catalyst container, 11...
・Reaction containers, 14 and 15... Ion exchange resin columns, 16... Concentration containers, 19... Traps, 20...
・Liquid level gauge, 21... Optical sensor, 22... High pressure hexagonal valve, 23... Pump for high performance liquid chromatography, 2
4...High performance liquid chromatography column, 26...
・Refractive index detector, 27...Syringe pump, 28...
- Vial, 29... High performance liquid chromatography eluent, 31... Hydrochloric acid reservoir, 32... Distilled water reservoir, 3
3... Methanol reservoir, 34... Sodium hydrogen carbonate aqueous solution reservoir, 35... Waste liquid reservoir, 36... Water inlet. Patent applicant: Takeda Pharmaceutical Co., Ltd. Patent attorney: Itsube Makino

Claims (1)

[Claims] (1) Connected to the respective supply means of ^1^1C-labeled hydrogen cyanide, acid aqueous solution, alkaline aqueous solution, 2,3:4,5-di-O-isopropylidene-D-arabinose solution, and Raney nickel catalyst or Raney alloy. a reaction vessel connected to the reaction vessel, an ion exchange resin column connected to the reaction vessel, a concentration vessel connected to the ion exchange resin column, a high performance liquid chromatography column connected to the concentration vessel; It is equipped with a connected glucose collection container, and first, an alkaline aqueous solution, ^1^1C labeled hydrogen cyanide and 2,3:4,5 are added to the reaction vessel.
-di-O-isopropylidene-D-arabinose solution to produce a solution containing 3,4:5,6-di-O-isopropylidene-D-glucononitrile in the reaction vessel, and then Raney nickel or Raney alloy catalyst is injected into a reaction vessel together with an acid aqueous solution, and 3,4:
5,6-di-O-isopropylidene-D-glucononitrile is reduced and simultaneously hydrolyzed to produce a solution containing ^1^1C-labeled glucose, and then this aqueous solution is passed through an ion exchange resin column, After transferring to a concentration container and concentrating the aqueous solution there, the obtained concentrated liquid was transferred to a high performance liquid chromatography column, and the obtained ^1^
An automatic synthesis device for 1C-labeled D-glucose, characterized in that it collects 1C-labeled glucose.