JPS6067436A - Apparatus for synthesis of 11c-carboxylic acid or alcohol - Google Patents

Abstract

PURPOSE:To provide a synthesizing apparatus composed of a reactor furnished with a heating and cooling means, a member for supplying the reaction gas, a member for supplying the reagents, and a member for separating the reaction product liquid, and capable of easily producing various <11>C-carboxylic acids or alcohols. CONSTITUTION:The reactor 10 is contained in the outer vessel 12, and heated or cooled by the hot-air blowing port 14 and heater 16, or the cooling air blowing port 18 and the refrigerator 20 attached to the outer vessel 12. The Grignard reagent, the water for hydrolysis, and the reducing agent are sealed in the syringes 32, 34, and injected into the reactor 10 in need by the air cylinders 36, 38. The <11>CO2 is introduced through the coupling 46, and supplied through the drier 48 to the reactor 10. After the completion of the reaction, the reaction product liquid separated into the upper organic layer and the lower water layer, is sucked with the pump 74. The boundary between the upper layer and the lower layer is detected by the sensor 76, and the pump 74 is stopped when only the lower layer is completely transferred to the separation vessel 80. Thereafter, the upper layer is supplied to another separation vessel 82.

Description

[Detailed Description of the Invention] Performing various measurements and analyzes using labeled compounds labeled with radioisotopes is a technique that has been widely applied in the fields of medicine, pharmacy, and other fields. ing. Conventionally,
These labeling compounds such as acetic acid, palmitic acid, etc.1
“IIC alcohols such as C-fatty acids and ethanol are
It was synthesized by reaction of l1co2 with Grignard reagent or further reduction. However, in the past, each labeling compound was synthesized using a separate apparatus; however, since there were many types of required labeling compounds, enormous equipment costs were required and handling was troublesome.

The present invention meets such requests. The purpose of this invention is to provide a synthetic method that can easily obtain various C-carboxylic acids or alcohols.

Namely, 1) the 11C-carboxylic acid/alcohol synthesis apparatus of the present invention comprises: a reactor equipped with a heating section, t3 and a cooling member; reaction 8: a reaction gas supply member supplying CO□; the reactor; a reagent supply member that supplies a Grignard reagent and a reducing agent to the reactor; a reaction product liquid separation member that is connected to the reactor and separates the reaction product liquid obtained in the reactor into an organic layer and an aqueous layer; the reaction product liquid It is characterized by comprising a recovery member that purifies and recovers 110-carvone or alcohol from the organic layer or aqueous layer separated by the separation member.

11°4 is a schematic diagram showing an embodiment of the synthesis apparatus of the present invention 1)
1, and the entire body is covered with a radiation gland shield such as lead.

The reactor 10 is housed in an outer container I2, and is connected to a heated air outlet 14 and a heater 3+ provided on the first side 12.
A heating element with a cooling air outlet 18 and a cooling element with a cooler (portex tube) 20 provided in the outer container 12 are arranged. Air is pumped from the coupling 22 through the valve 24, heated by the heater 16, and heated air is blown out through the insulated pipe 26. : The reactor 10 is heated by blowing from 114. Similarly, the reactor 10 is cooled by pumping air into the cooler (portex tube) 20 through the valve 2B and blowing out the cooling air from the cooling air outlet 18. 30 represents a needle valve.

The reactor 10 contains a Grignard reagent, water for hydrolysis, and LiAll1. A syringe (2, 34) is provided in which a reducing agent such as the following is sealed, and the Grignard reagent is extruded into the reactor 10 as needed by the air cylinder 36.3B.Reactor 10 It is preferable that the connection is made such that the injection side stands up on the silicone rubber 11-shade so that it is easy to handle and does not leak.

Braking valve 42. /l/l and operates the air cylinders 36 and 38 to release the syringes 32 and 3t.
The contents of r are fed to reactor 10. I I i:l:
A reflux capacitor is shown.

” co□ was introduced from coupling 4G, and i'20
．． The reactor 1 passes through a dryer 48 such as a tube and a valve 50.
0.

The vials 52 and 54 can contain necessary solvents, hydrochloric acid, etc. necessary for hydrolysis. These stored items are valves! +6158 by applying pressure nitrogen gas from coupling 40 to valve 60.6.
2. It is supplied to the reactor 10 via the inlet 64. 6G
indicates a flow controller, and 68 indicates a flow meter.

The reaction product liquid separation member includes a pump 74 and a sensor 76, and communicates with the reactor via channels 70,72.

The pump 74 sucks the reaction product liquid separated into two layers, an organic layer and an aqueous layer, in the reactor 10 after the reaction is completed.

At this time, the boundary between the lower layer and the upper layer is detected by the sensor 76, and only the lower layer is sent to the first receiver 80. When the suction of the lower layer is finished, the pump 74 is stopped and the valve 78 is closed.
is opened and the two layers are fed to the second separation receiver 82 by the pressure of nitrogen gas from the coupling 40. sensor 76
A capacitive sensor or the like is used to detect a change in the wicking liquid from hydration to organic phase or vice versa.

Further, a constant displacement pump is preferable as the pump, and a valve may also be provided at the front stage of the pump.

The aqueous layer or organic layer (J
Solids are removed and sterilized through a filter 84, J+1;
IIV container 8 covered with a radiation shield 88 such as a button
It will be collected within 6 days. 1st separation container 80/7) 4 french ro v
I now rlJI? Susu! Clean and interesting b11zu
No. 1 Shitun - If necessary, a valve may be provided at the downstream of the first separation vessel 1.80. Furthermore, it is also possible to provide means for purifying the & layer or aqueous layer, and the second separation container 82 is connected with a separation column 92. The organic layer or aqueous layer fed to S 82 passes through a filter 90 and a switching valve 94.
Send it to the notary box 1192 filled with EP-PAC etc. A washing liquid such as n-hexane is supplied to the separation column 1192 from a vial 98, and a one-volume liquid such as ethanol is supplied from a vial 104. Impurities are discharged through a line 10B, a trap 110, and a valve 112. 4Jli is taken out from the coupling 114 for. A vacuum can also be drawn via the coupling 112. On the other hand, 1] Target 1:1' is collected into a collection container 1211 covered with a radiation shield 126.

100.102.1] 8,120 represents a valve, 1
16 indicates a soda lime tube. Of course, a separation column can also be installed downstream of the first separation container 80.

Furthermore, in this embodiment, a distillation means is provided, which includes a reaction 1i 710 serving as a distillation vessel and a condenser 128 connected thereto. Cooling air is supplied to the condenser 128 from a cooler 130 such as a The separated aqueous layer or water layer is sent to the reactor 10 from the first separation vessel 80 via valve 81 and from the second separation vessel 82 via valve 78.

83.85 is a valve for controlling the pressure N2 gas from the coupling 40. The aqueous layer or organic layer sent to the reactor 10 is heated by hot air from the heater 1G, condensed in the condenser 12B, and the target product is recovered in the recovery container 136.

138, 1/IQ indicates a cleaning liquid storage container constituting the cleaning system, and a cleaning liquid such as water or alcohol is stored therein. After the synthesis is completed, this liquid is sent to the reactor 10 via the valve 142 and the line 64, and further to the 1.1' and second separation vessels aO, 82 to wash the inside of the apparatus. r1shi,
Get ready for the next synthesis. With this device, the synthesis system can be kept clean in this way, and it is also possible to easily synthesize iλ-sensitive compounds intended for administration to the human body by intravenous injection or the like.

Examples of how this device is used for a few IIC fatty acids and alcohols will be described below.

(t) ``Synthesis of c-palmitic acid CI+3 (C112) A Grignard sample prepared by dissolving 14M of Ilr in 1 to 50 chloride hydrofuran or diethyl ether is placed in the syringe 32, and this is injected into the reactor 10.Next, ``CO2 is reacted with N2 gas as a carrier through valve 47.50! A Grignard reaction is carried out by introducing into H+O and bubbling it. After the reaction, the generated C11. (C112), 4" COMHr3r is supplied with lN-11CI+ from vial 52 and hydrolyzed to obtain lIC-palmitic acid. After adding n-hexane etc. from vial 54 as necessary, leave it still.
Separate into an organic layer and an aqueous layer. -], this reaction product liquid is sucked out by the pump 74, and the organic J? Detecting the change in the flow rate to 'J, the aqueous layer is transferred to the first separation container 80 (container 80), and the organic layer is transferred to the second separation container 82.
Niso] Separate each. Then, separate the organic layer through column 9.
2, remove impurities such as pentadecyl alcohol and pentadecane from vial 98 with diethyl ether over n-hexane, and feed diethyl ether or ethanol containing acetic acid from vial 104, and then remove lIC-palmitic acid. elute and collect it in the collection container 126.
to be collected.

(2) Synthesis of lIC-acetic acid (A Grignard reagent prepared by dissolving IflMgnr in tetrahydrofuran or diethyl ether is stored in the fringe 32 and injected into the reactor 10, and IC is carried out in the same manner as in the case of lC-palmitic acid. -Synthesize acetic acid.Methane gas generated during hydrolysis is released from the discharge coupling 1111 via the valve 13.1]8.Next,
The reaction product is sucked out with a pump 74'C, and the lIC-acetic acid contained in the aqueous layer is poured into the first portion 1i11 ['7\] 1
iiiE L, solid impurities are removed by a filter 84, and collected into JR (i).

(3) 11 (Synthesis of ethanol) A chilled solution of Grignard reagent (CHi MgBr 1-nitrofuran 1: or diethyl ether solution) was stored in the cylinder 32. The Grignard reagent was injected into the reactor 10. Noji, valve 47.!'io from l1co2
1. Introduce N2 gas as a carrier and perform the Grignard reaction by bubbling. At this time, from the cooler 20,
Cooling air is supplied into the outer container 12 to improve the reaction rate.
At the same time, the cooling air is sent to the reflux condenser 1.
1 to prevent the IF medium from scattering. After the reaction is completed, LjAIIl is injected from the syringe 34 for reduction. At this time, N2 gas is bubbled through valves 49 and 50 to promote the reaction. Next, 100 ml of ethanol is supplied from the vial 52 for hydrolysis, and the synthesis of +IC-ethanol is completed. Then, it is sucked out by the pump 74 and the aqueous layer containing lIC-ethanol is collected in the first fraction 11 volumes B:'f 80. This aqueous layer is returned to the reactor 10 via valve 81 and stream v870.

Note that, prior to this, the reaction i()+6 was heated while introducing N2 gas to remove the flame solvent from the reactor 10. The organic solvent is recovered together with ethanol in the next step of distillation, and is cooled down to 41 ml per human body. ii + I n
is heated and allowed to stand still to obtain "C-ethanol" in the recovery container 136.As shown in the figure, according to the apparatus of the present invention, C1,
,,,"CO (fatty acid with the form 'i11, C, n-,
II, n-, “alcohol with the form CI+2011,
In addition, unsaturated fatty acids such as oleic acid and linoleic acid, alcohols derived from these, and alcohols such as oleic acid and linoleic acid.
Carboxylic acid, 7 alcohol, etc. Grignard sample and IICQ
The carboxylic acid and alcohol obtained from the reaction with 2 can be synthesized.

However, by integrating the reactor, splitting means, collection means, etc., it is possible to reduce loss, and it is also possible to synthesize a variety of target substances with a simple operation. Automatic synthesis is also possible by installing Progera 11 on a computer or the like.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing an embodiment of the synthesis apparatus of the present invention. 10.Reactor 16..Heater 20..Cooler 32.34..Syringe 74.
...Bomb 76...Sensor 80...First cutting volume 8-2...Second sieve container 86.124,1
36...Collection container

Claims (1)

[Claims] 1. A reactor in which a Jlll thermal component, t'; and a cooling member are arranged; a reaction gas supply member that supplies IlCo2 to the reactor; a reagent supply member that supplies a Grignard reagent and a reducing agent to the reactor; ; A reaction product liquid separation section (1; l + 亥 reaction product liquid 9f) which is connected to the reactor and separates the reaction product liquid obtained in the reactor into an aqueous layer and an aqueous layer; A C-carboxylic acid/alcohol synthesis device equipped with a recovery member that purifies and recovers C-carboxylic or al-ni-l from the separated organic layer or aqueous layer. .