JP2828853B2 - Acetic acid synthesis method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for synthesizing acetic acid,
In particular, the present invention relates to a method for synthesizing acetic acid labeled with ¹¹ C which is a radioactive isotope having a short half-life.

[0002]

2. Description of the Related Art In recent years, in the field of nuclear medicine, diagnosis is performed by positron CT (computer tomography). As isotopes with short half-lives, ¹¹ C, ¹³ N, ¹⁵
O, ¹⁸ F and the like have come to be used.

The half-life of ¹¹ C is 20 minutes, and the half-life of ¹³ N is 1
0 min, the half-life of ¹⁵ O is 100 seconds, the half-life of ¹⁸ F is 110
Minutes. Of these isotopes, ¹¹ C, ¹³ N, ¹⁵ O
Is a kind of element that constitutes a living body and is not a foreign substance to a living body, and thus has a high utility value. Also, ¹⁸ F has an advantage that it can be easily used because of its relatively long half-life.

[0004] Positron nuclides with a short half-life must be synthesized in a hospital in order to be efficiently administered to a subject. That is, a cyclotron for producing a positron nuclide, a synthesizing apparatus for synthesizing a radiopharmaceutical containing a positron nuclide, and a camera for taking a tomographic image after administering the positron nuclide are integrated, and tomography diagnosis is performed on the spot.

[0005] Acetic acid labeled with ¹¹ C, for example, can measure blood flow as well as oxygen metabolism in the myocardium, and is effective in diagnosing pathological conditions of the myocardium. In a cyclotron, ¹¹ C can be formed in the form of CO ₂ .

FIGS. 4 and 5 show examples of the synthesis of ¹¹ C-labeled acetic acid according to the prior art. FIG. 4 shows the steps of the synthesis in chronological order, and FIG. 5 schematically shows an apparatus for performing the synthesis.

First, a step of preparing an ether solution of CH ₃ MgBr shown in FIG. 4A is performed by using a cooler 15 shown in FIG.
The reaction is performed by preparing an ether solution of CH ₃ MgBr, which is a kind of the Grignard reaction reagent, in the reaction vessel 11 cooled by the above method.

Next, the bubbling step of ¹¹ CO ₂ shown in FIG. 4 (B) is performed by flowing the target gas ( ¹¹ CO ₂ ) to the reaction vessel 1 through the flow meter 12, the valve V1, and the pipe T1 shown in FIG.
1 and bubbling in an ether solution of CH ₃ MgBr.

By this bubbling, a Grignard reaction represented by CH ₃ MgBr + ¹¹ CO ₂ → ¹¹ CH ₃ COOMgBr proceeds, and an organic solution of the compound CH ₃ COOMgBr labeled with ¹¹ C is formed.

Next, in the step of adding HCl shown in FIG. 4C, an inert gas is pressurized in the hydrochloric acid container 13 shown in FIG.
The reaction is carried out by introducing the reaction mixture into the reaction vessel 11 through the reaction vessel 2.

By adding HCl, CH ₃ ¹¹ COOMgBr + HCl → CH ₃ ¹¹ COOH +
The reaction of Mg ²⁺ + Br ⁻ + Cl ⁻ proceeds, and acetic acid labeled with ¹¹ C is synthesized.

At this time, as shown in FIG. 4D, an organic layer of ether and a water layer are formed separately in the reaction vessel 11. Acetic acid can be included in the organic layer by adjusting the amount of water of the aqueous HCl solution to be added.

The step of taking out only the organic layer out of the separated water layer and organic layer is performed by using a valve V4a, an organic solvent / water separation sensor 26, a pump 27, and a valve V4b. Only the aqueous layer through the waste tank 2
8 to be collected. After removing the aqueous layer, the organic layer is put back into the reaction vessel 11.

Next, NaO is added to the organic layer shown in FIG.
The addition of H is performed by applying a pressure of an inert gas to the sodium hydroxide container 25 and introducing an aqueous solution of sodium hydroxide into the reaction container 11 via the valve V8 and the pipe T8.

By adding NaOH, CH ₃ ¹¹ COOH + NaOH → CH ₃ ¹¹ COONa + H
The reaction of ₂ O proceeds, and acetic acid becomes sodium acetate.

At this time, as shown in FIG. 4 (F), the solution in the reaction vessel 11 is again separated into an organic layer and an aqueous layer, but sodium acetate is distributed in the aqueous layer. The aqueous layer is separated and taken out by connecting the solution in the reaction vessel 11 to the pipe T via the valve V4a, the organic solvent / water separation sensor 26, the pump 27, and the valve V4b.
This is carried out by feeding from 4 into the collecting container 17.

The organic solvent / water separation sensor 26 detects the interface between the aqueous layer and the organic layer. The aqueous layer is stored in the collection container 17 and the organic layer is stored in the waste liquid tank 28. In this way, the aqueous layer in which sodium acetate is dissolved is collected in the collection container 17.

The heating step shown in FIG.
This is performed by heating the heater 19 surrounding the heater 7. By heating, the ether remaining in the aqueous solution evaporates as shown in FIG. The evaporated ether is discharged via the pipe T7 and the valve V7.

Next, the addition of HCl shown in FIG.
The hydrochloric acid container 29 is pressurized with an inert gas, and a valve V9,
This is performed by supplying hydrochloric acid to the collection container 17 via the pipe T9.

By adding HCl, CH ₃ ¹¹ COONa + HCl → CH ₃ ¹¹ COOH + Na
The reaction of Cl 2 proceeds and acetic acid is formed again.

At this time, the neutralization step shown in FIG. 4 (J) is performed simultaneously, and the solution is adjusted from neutral to acidic. Next, as shown in FIG.
PH is adjusted by adding ₃ solutions, etc.
The sterilization filtration shown in (L) is performed, and as shown in FIG. 4 (M), the reaction product is collected through a valve V6 and a pipe T6. Thus, acetic acid labeled with ¹¹ C can be obtained.

In the method of synthesizing acetic acid described above, liquid-liquid extraction is performed twice, as shown in steps (D) and (F) of FIG. ¹¹ C is a radioisotope, and the above-described reaction must be performed in a shielded space for radioactivity protection. For this reason, it is necessary to automate the reaction, but the liquid-liquid extraction is complicated and the operation is not suitable for automation.

Further, if it is attempted to carry out such a reaction in an automated process, the time required for the reaction is about 35 to 40 minutes, and the ¹¹ C whose half-life is as short as 20 minutes is reduced to about 1/4.

[0024]

As described above,
The conventional method for synthesizing ¹¹ C-labeled acetic acid requires complicated operations and requires a relatively long time to complete the reaction.

An object of the present invention is to provide a method for synthesizing ¹¹ C-labeled acetic acid, which is simple and can be performed in a short time.

[0026]

¹¹ The method of synthesis C were labeled acetic acid of the present invention solving the problem to means for the], in addition a step of reacting ¹¹ CO ₂ to Grignard reagent, a hydrochloric acid Grignard reagents react with ¹¹ CO ₂ Hydrolysis And generating acetic acid, heating the hydrolyzed liquid and evaporating the acetic acid together with the solvent, and collecting the evaporated acetic acid.

[0027]

The acetic acid can be recovered by reacting the Grignard reagent ¹¹ CO ₂ , adding hydrochloric acid to generate acetic acid, and then evaporating the acetic acid together with the solvent without performing liquid-liquid separation. Since no liquid-liquid separation is performed, the operation is simplified, and the time required for the entire reaction is reduced.

[0028]

1 and 2 show the synthesis of ¹¹ C-labeled acetic acid according to an embodiment of the present invention. FIG. 1 shows the synthesis reaction in chronological order, and FIG. 2 schematically shows a synthesis apparatus for performing the synthesis reaction.

First, the step of preparing a diethyl ether solution of CH ₃ MgBr, which is a kind of the Grignard reagent, shown in FIG. 1A is performed by storing the ether solution of the Grignard reagent in the reaction vessel 11 of FIG. .

Next, the bubbling step of ¹¹ CO _{2 into} the Grignard reagent shown in FIG. 1 (B) is performed in the reaction vessel 1 shown in FIG.
This is performed by bubbling ¹¹ CO ₂ gas into 1. ¹¹ CO ₂ gas is the target 1 filled with nitrogen gas.
By colliding proton particles accelerated with a cyclotron at 0, and releasing α particles from the combined (nitrogen + proton), ¹¹ C is generated and obtained by combining with oxygen present in the target 10 to the extent of a trace. . This ¹¹ CO ₂ is collected in a pipe-shaped container immersed in liquid argon.

The thus obtained ¹¹ CO ₂ was passed through a flow meter 1
2. Cooler 1 from pipe T1 via pinch valve PV1
Bubbling is performed by supplying the reaction vessel 11 cooled in 5 to the reaction vessel 11. By bubbling ¹¹ CO _2, to perform a Grignard reaction _{^{CH 3 MgBr + 11 CO 2 →}} CH 3 11 COOMgBr.

Next, the HCl addition step shown in FIG. 1C is performed by applying a pressure of an inert gas to the hydrochloric acid container 13 and supplying hydrochloric acid to the reaction container 11 via the pinch valve PV2 and the pipe T2. Do.

By adding HCl, CH ₃ ¹¹ COOMgBr + HCl → CH ₃ COOH + M
g ²⁺ + Br ⁻ + Cl ⁻ is reacted to synthesize acetic acid. The steps up to this step are the same as the steps in the conventional technique.

Next, the heating step shown in FIG. 1D is performed by heating the reaction vessel 11 with the heater 14.
From the reaction vessel 11, evaporating substances such as a solvent and acetic acid evaporate and are sent to a collection vessel 17 via a pipe T4 and a pinch valve PV4. In the collection container 17, NaHCO ₃
Keep the liquid.

By this evaporation step shown in FIG.
Residue remains in the reaction vessel 11, and the evaporant is transferred to the collection vessel 17.
Run. As shown in FIG. 1 (F), it is supplied to the collection container 17.
The evaporated evaporate is NaHCO_ThreeTrapped in liquid. What
The trapped acetic acid is CH_Three ¹¹COOH + NaHCO_Three→ CH_Three ¹¹COONa
+ H_TwoCO_Three Is converted to sodium acetate. This time,
The solution is excess NaHCO _ThreeKeeps the pH constant.
Dripping.

Next, as shown in FIG. 1 (G), the collection container 17 is heated by a heater 19 so that the collection container 17 is heated.
The solvent inside is evaporated. As shown in FIG. 1 (H), evaporable substances such as ether and water evaporate from the collection container 17, leaving sodium acetate.

Next, the physiological saline shown in FIG. 1 (I) is added to the physiological saline container 18 shown in FIG. 2 by pressurizing an inert gas, and the physiological saline is supplied via the pinch valve PV8 and the pipe T8. This is performed by supplying a saline solution to the collection container 17.

After the sterile filtration shown in FIG. 1 (J) is performed, the reaction product is recovered as shown in FIG. 1 (K). The reaction product is collected in the container 20 through the filter.

Although the case where methylmagnesium bromide CH ₃ MgBr is used as the Grignard reagent has been described, methylmagnesium chloride or the like can be used similarly. As the organic solvent, other organic solvents such as tetrahydrofuran may be used in addition to diethyl ether.

Hereinafter, a specific example of acetic acid synthesis will be described. 0.5 ml of a 1 mol solution of methylmagnesium chloride in tetrahydrofuran is poured into the reaction vessel 11 at room temperature. 1 ml of 7% sodium bicarbonate (Meiron solution) is injected into the collecting container 17.

¹¹ CO ₂ produced in a small cyclotron
Is collected in a pipe-shaped container once immersed in liquid argon or the like, and ¹¹ CO ₂ in the target gas is collected. Thereafter, while cooling the reaction vessel 11 with the cooler 15, ¹¹ CO ₂ is introduced into the reaction vessel to cause a Grignard reaction. Immediately after the introduction of ¹¹ CO ₂ , 0.5 ml of 1N hydrochloric acid is injected into the reaction vessel 11 to produce acetic acid labeled with ¹¹ CO ₂ .

While introducing nitrogen gas into the reaction vessel 11 at a rate of 200 ml / min, the reaction vessel 11 was heated by the heater 14.
^The acetic acid labeled with ¹¹ C is evaporated and transferred to the collection container 17.

Acetic acid is trapped in the Meilon solution in the collection container 17 and collected as a sodium salt. After about 5 minutes, the transfer is completed, the collection vessel 17 is heated, and the accompanying tetrahydrofuran solution and recovery aqueous solution are evaporated.

Thereafter, a physiological saline solution was injected into the collecting container 17 to produce acetic acid labeled with ¹¹ C, and the acetic acid was filtered through a filter and collected in the container 20. Cyclotron energy of 18 MeV, irradiation current of 10 μA, irradiation time of 5 minutes, from recovery of target gas to recovery of acetic acid in about 15 minutes, 2.0
GBq of acetic acid was recovered. The conversion was 70-80% based on ¹¹ CO ₂ trapped in the Grignard solution. The operation of acetic acid synthesis was simplified and the required time was shortened.

The radiochemical purity of the recovered solution was measured by high performance liquid chromatography. The analysis chart is shown in FIG. Radiochemical purity was over 98%. The recovered solution contained 0.02 mg of magnesium and contained only about 2 mg of chloride ions, and was of a suitable quality as a solution for injection.

In the synthesizing apparatus shown in FIG. 2, the pipes T1 to T8 are preferably constituted by disposable extension tubes. Further, it is preferable to use the pinch valves PV1 to PV8 which press the extension tube from the outside and shut off the flow path. When a valve having a mechanism inside such as an electromagnetic valve is used, the operation of the valve may be insufficient due to solidification from a transferred liquid or gas.

Incidentally, as shown in FIG.
And the heaters 14, 19 and the cooler 15 are configured separately, so that the piping system and the heater / cooler system can be separated,
Various syntheses can be easily and selectively performed in the same apparatus.

The present invention has been described in connection with the preferred embodiments.
The present invention is not limited to these. For example,
It will be apparent to those skilled in the art that various modifications, improvements, combinations, and the like can be made.

[0049]

As described above, according to the present invention,
The simplified procedure provides a method of synthesizing ¹¹ C-labeled acetic acid that is easy to automate.

Further, the reaction time required for synthesizing acetic acid labeled with ¹¹ C is reduced, and the residual ratio of ¹¹ C is improved.

[Brief description of the drawings]

FIG. 1 is a flowchart illustrating a method for synthesizing ¹¹ C-labeled acetic acid according to an embodiment of the present invention.

FIG. 2 is a schematic diagram of a synthesizing apparatus for performing the synthesizing method shown in FIG.

FIG. 3 is a graph showing measurement results of synthesized acetic acid by high performance liquid chromatography.

FIG. 4 is a flowchart showing a method of synthesizing ¹¹ C-labeled acetic acid according to the prior art.

FIG. 5 is a schematic view of a synthesizing apparatus for performing the synthesizing method of FIG. 4;

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 10 Target 11 Reaction container 12 Flow meter 13 Hydrochloric acid container 14 Heater 15 Cooler 17 Collection container 19 Heater 20 Container T piping PV Pinch valve

Claims (2)

(57) [Claims] 1. A step of reacting a Grignard reagent with ¹¹ CO ₂ , a step of adding hydrochloric acid to the Grignard reagent reacted with the ¹¹ CO ₂ and hydrolyzing to form acetic acid, and heating the hydrolyzed liquid to form acetic acid. A method for synthesizing ¹¹ C-labeled acetic acid, comprising: evaporating acetic acid together with a solvent; and collecting the evaporated acetic acid. 2. The method for synthesizing acetic acid according to claim 1, wherein the Grignard reagent is an organic solvent solution, and the acetic acid collecting step includes trapping acetic acid in a sodium hydrogen carbonate solution.