JPH0663389A - Automatic synthetic reactor - Google Patents

Abstract

PURPOSE:To automatically execute a prescribed reaction by arranging a liquid temperature sensor and a pH sensor in a reacting vessel and controlling in accordance with the detecting value of the sensor so as to supply a reagent only when the liquid temp. and pH are in a certain range. CONSTITUTION:The liquid temperature sensor TC1 and the pH sensor PHS are provided in the inside of the reacting vessel 11 to supply the reagent from plural reagent vessels Y1-Y4 via pipe line and solenoid valves V1-V4 opening and closing in accordance with the detecting signal from the sensors are provided in the pipe line. And timers TM1-TM4 are connected to the solenoid valves to make open and close and at the same time the timers are turned on and off by each of the detecting signals of the temperature sensor and the pH sensor. And a heat medium vessel 12 surrounding the reacting vessel 11 is provided and the temp. of the heat medium circulated to the vessel 12 is controlled by the detecting value of the liquid temperature sensor TC1 or a heat medium temperature sensor TC2 so as to be a prescribed temp.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an automatic synthesis reaction apparatus, and more particularly, to an apparatus for reacting a reagent while maintaining a temperature or a temperature and a pH within a certain range. In contrast, a plurality of liquids can be simultaneously dropped from a plurality of reagent containers.

[0002]

2. Description of the Related Art Generally, in an automatic synthetic reaction apparatus, basic compounds necessary for synthesis are sequentially executed based on a synthetic procedure to synthesize a desired compound. That is, various operations such as injection of reagent or solvent, dropping, temperature change, stirring, extraction, concentration, washing, drying, pH control, distillation, and reflux are performed in combination. In addition, devices for purifying and collecting the synthesized compounds can be used in combination.

[0003]

However, an automatic synthesis reaction apparatus having all of the above-mentioned functions has a large size and a high price, and a special exhaust system for the apparatus is required.

Further, in the conventional automatic synthesis reaction apparatus, the temperature adjustment and the pH adjustment of the solution in the reaction vessel are generally performed in separate reaction vessels, and therefore, the solution is transferred between a plurality of reaction vessels. There was a need. Further, there has been no means for automatically supplying a required amount of reagent when the temperature or the temperature and the pH are within the required range while automatically adjusting the temperature or both the temperature and the pH. Therefore, when it is necessary to control the reaction while keeping the temperature of the liquid in the reaction vessel or the temperature and pH within a certain range, an expert usually measures the temperature and pH of the liquid in the reaction vessel while adjusting the temperature. In addition, since the pH is adjusted, and the reagent is dropped and replaced in each reaction vessel manually, it is troublesome and accurate control cannot be performed, and there is a problem that the yield deteriorates as described below. It was

That is, when it is necessary to control the reaction when the pH is within a certain range and the temperature of the reaction solution is within a certain range, if the temperature is excessively cooled beyond the certain range, the progress of the reaction is delayed. If the optimum reaction cannot be performed and the temperature of the reaction solution rises sharply on the contrary, the temperature of the reaction solution rises due to the time delay of cooling the reaction container. For this reason, the reaction cannot be carried out under the optimum conditions, and there is a drawback that the yield is deteriorated because of unexpected side reaction or decomposition.

Furthermore, in the conventional automatic synthesis reaction apparatus, simultaneous dropping of two or more liquids was not possible in the dropping reaction. That is, the present situation is that two or more reagent containers are not dropped simultaneously into one reaction container through a pipe, but are staggered in time and dropped separately. As a result, conventionally, there has been a problem that a reaction cannot always be performed under a constant condition at a constant ratio.

Due to the above-mentioned problems, conventionally, while keeping the temperature within a certain range and keeping the pH value within the certain range, it is possible to automatically control the dropping of the two liquids under the same conditions. It was almost impossible.

Further, in the conventional automatic synthesis reaction apparatus, it was not possible to control the temperature to be precisely raised or lowered with a very slow temperature gradient. Therefore, for example, when the temperature suddenly rises from the state of reacting at a low temperature, there is a possibility that the unreacted substance or the target product may be decomposed. When the temperature gradient is large as described above, unreacted substances or target products are likely to be decomposed, which sometimes leads to a decrease in synthesis yield. On the contrary,
Even if it is in an unreacted state, if the temperature is raised moderately, the reaction may progress little by little and the yield may increase. It was not possible to control the temperature of the reaction solution with the above temperature gradient.

The present invention has been made in view of the above-mentioned problems, and provides a device which can be used effectively in a narrow laboratory by downsizing the device and enabling it to be installed on a laboratory table or in a draft. Is intended. In addition, cost reduction is achieved by reducing the number of parts that make up the device,
It is intended to provide an automatic synthesis reaction device capable of performing highly accurate reactions with few failures.

Further, according to the present invention, the reagent can be automatically dropped into the reaction vessel to carry out the reaction only when the temperature of the reaction solution is within a certain range, or only when the temperature and pH are within a certain range. In addition, the present invention also provides an automatic synthesis reaction device capable of simultaneously dropping from two or more reagent containers to the above reaction container under the same conditions.

[0011]

The present invention provides an apparatus for automatically carrying out a synthetic reaction by supplying a reagent from a reagent container through a pipe to the inside of a reaction container surrounded by a heat medium container,
While a liquid temperature sensor is provided in the reaction vessel, an opening / closing valve is provided in the pipe, and a temperature control means for a heat medium to be inserted between the heat medium vessel and the reaction vessel is provided, and
The on-off valve and the temperature control means are operated in response to a detection signal from the liquid temperature sensor to control the liquid temperature in the reaction container within a predetermined constant range, and to control the liquid temperature in the reaction container within the constant temperature range. It is an object of the present invention to provide an automatic synthesis reaction device, which is provided with a control circuit for operating the on-off valve so as to supply a reagent.

In the automatic synthesis reaction apparatus of the present invention, a heat medium temperature sensor is provided between the heat medium container and the reaction container, and the heat medium temperature control means is operated according to a detection signal from the heat medium temperature sensor. It is also possible to improve the response of the temperature control of the heat medium temperature and to quickly control the temperature in the reaction vessel within a predetermined constant range.
In particular, between the heat medium container and the reaction container, while circulating the cooling medium of the required temperature stored in the heat medium tank, the heat medium flow passage in the gap between the outer surface of the reaction container and the inner surface of the heat medium container. It is preferable to arrange a heating means such as a heater in the above and to control the temperature so that the temperature becomes a required temperature by heating the cooling medium by the heating means. With this configuration, when the solution temperature in the reaction vessel rapidly changes due to the reaction heat, the liquid in the reaction vessel can be controlled by controlling the temperature of the heat medium locally in the heat medium vessel. The temperature can be quickly adjusted to reach the required temperature.

In addition, in the automatic synthesis reaction apparatus of the present invention, the pH of the liquid is directly measured together with the liquid temperature sensor in case the liquid in the reaction vessel needs to react when the temperature and pH are within a certain range. It is preferable to provide a pH sensor for positive detection and to fill at least one of the reagent containers connected to the reaction container through a pipe with a pH adjusting reagent. When the pH of the solution in the reaction container is controlled within a certain range, and when it is necessary to drop the reagent into the reaction container to react when the pH is within the certain range, the control circuit detects the detection signal from the pH sensor. According to the above, the on-off valve is operated so that the pH is within the required constant range, and the pH adjusting liquid is supplied to the reaction vessel, and when the liquid temperature and pH in the reaction vessel are within the required constant range, other The reagent is controlled to be supplied from the reagent container to the reaction container.

The opening / closing valve provided in the pipe connecting the reaction container and the reagent container is an electromagnetic valve, and a timer for operating the electromagnetic valve is provided, and the timer is set by the operation signal from the control circuit. The solenoid valve is opened for the required time. In addition, the set time by the timer is manually operable so that the opening time of the on-off valve can be finely adjusted as necessary.

The automatic synthesis reaction apparatus of the present invention is particularly characterized in that it is possible to simultaneously drop a plurality of reagents from a plurality of reagent containers into a reaction container,
Therefore, a plurality of reagent containers are connected to the reaction container via piping provided with solenoid valves, and a timer is connected to each solenoid valve, and the control circuit causes the timer to keep the solenoid valve for a certain period of time. While opening and closing at the same timing at intervals, the timer is turned on and off by the detection signals of the liquid temperature sensor and the pH sensor, and when the temperature and pH of the solution in the reaction container are within the required fixed range, multiple The reagent is supplied simultaneously.

The supply of the reagent from the reagent container to the reaction container is carried out by dropping the reagent under a constant pressure so that a required amount of the reagent can be dropped into the reaction container with high accuracy. Furthermore, this apparatus is also provided with an automatic cleaning means for reagent containers and reaction containers.

[0017]

As described above, in the automatic synthesis reaction apparatus of the present invention, since the liquid temperature sensor is directly arranged in the reaction container,
The temperature change in the reaction liquid can be directly measured, and the reagent can be dropped when the liquid in the reaction container is within a certain temperature range. Similarly, since the pH sensor is arranged inside the reaction container, it is possible to control the dropping under the condition within a certain pH range. That is, both the liquid temperature sensor and the pH sensor are arranged inside the reaction container, and the reagent is supplied only when the liquid temperature is within a certain range and the pH is within a certain range according to the detection values from these sensors. The desired reaction can be automatically achieved because the control is performed so that

Further, an on-off valve, which is an electromagnetic valve provided in a pipe from the reagent container to the reaction container, is operated by a timer, and the output switch of the timer is turned on for a set short time, and then immediately shut off. Since it has the function of a multivibrator, the solenoid valve operates only for this limited time and drops an accurate amount of the reagent. Further, even if the amount of the liquid changes, the liquid is pushed out at a constant pressure, so that the required amount of reagent can be surely dropped.

Further, a plurality of reagents can be dropped simultaneously from the plurality of reagent containers into the reaction container by the opening operation of the electromagnetic opening / closing valve. In the dropping method of this device, the setting time of the twin timer dial (the time it is on) even during the dropping operation.
By finely adjusting, the amount of one drop can be controlled.

Furthermore, the temperature of the heat medium is controlled according to the detection values of the liquid temperature sensor provided inside the reaction vessel and the heat medium temperature sensor provided between the reaction vessel and the heat medium vessel. Therefore, for example, gentle temperature control such as increasing the temperature at 1 ° C. for 3 minutes can be performed.

Further, the present automatic synthesis reaction apparatus can perform temperature adjustment, pH adjustment and synthesis reaction in one reaction vessel, and, by exchanging the reaction vessel with one having a different size, a small volume can be obtained. Capable of synthesizing up to large scales.

[0022]

Embodiments of the present invention will now be described in detail with reference to the drawings. FIG. 1 is a schematic configuration diagram of an automatic synthesizing apparatus according to the present invention, and the automatic synthesizing apparatus is installed in a draft. The outside of the reaction container 11 is surrounded by a heat medium container 12 with a predetermined gap therebetween.
The upper end opening of 2 is closed using a silicone rubber member. The reaction container 11 and the heat medium container 12 are made of transparent glass so that the reaction status can be confirmed from the outside. The heat medium container 12 has a vacuum heat insulating structure, and is provided with ports 13 and 14 for supplying and discharging silicon oil as a heat medium in a gap portion between the reaction container 11 and the heat medium container 12.

A lid 15 is attached to the upper end opening of the reaction container 11 by a one-touch joint 16 with Teflon packing interposed therebetween. The lid 15 has a stirring shaft to be described later, p
A hole is formed through which a pipe connected to the mounting shaft of the H sensor and the liquid temperature sensor and the reagent container is passed.

A lid 15 is inserted through the center of the reaction vessel 11 to hang down a rotary shaft 18 of the stirrer. A stirrer 17 is attached to the lower end of the rotary shaft 18, and the stirrer 17 is placed at the center of the bottom of the reaction vessel 11. It is located in. A pulse motor M is connected to the rotating shaft 18 so that the rotating shaft 18 is alternately rotated in one direction or in the arrow direction.

In the figure, TC1 is a liquid temperature sensor for detecting the temperature of the liquid in the reaction vessel 11, and PHS is a pH sensor for detecting the pH of the liquid in the reaction vessel 11. It hangs inside. TC2 is a heat medium temperature sensor that detects the temperature of the heat medium in the heat medium container 12.

The heater 19 is mounted inside the heat medium container 12 on the back side of the bottom surface of the reaction container 11, the magnet spinner 20 is charged, and the spinner 20 is rotated by the rotating magnetic force of the stirrer 21 arranged on the bottom side of the heat medium container 12.
I am trying to rotate. In addition to rotating the rotary shaft 18 from above by the motor M to rotate the stirrer 17, the rotary shaft is removed and a stirrer (spinner) is put into the reaction vessel 11, and the stirrer is installed by a stirrer below. You may make it rotate and agitate the solution in the reaction container 11. (See Figure 6)

Y ₁ to Y ₄ are containers for reaction reagents and have a pH of
When it is necessary to adjust pH within a certain range, one of the above-mentioned containers (in this embodiment, container Y ₄ ) is filled with the pH adjusting liquid. The container may also be a solvent container depending on the purpose. The reagent container is arranged above the reaction container 11 so that reagents, solvents and the like are introduced into the reaction container 11 through respective pipes. The piping of the vessel Y _1, Y _4, provided with a respective pair of solenoid valves V1, V4, and controls the introduction of liquid. The solenoid valves V1 and V4 are the circuits shown in FIG.
It is controlled by 1, PS12, PS51, PS52.

The switch PS12 controls opening and closing by the CPU signal of the control circuit of the reaction device, and PS11 is the timer TM1.
In ON time of the time is controlled, the reagent in the container Y ₁ PS11
The solenoid valve V1 is controlled so as to be charged into the reaction container 11 only when and PS12 are simultaneously supplied. Switch PS5
2 controls the opening and closing by the CPU signal of the control circuit of the reaction device,
In PS51, the time of entry is controlled by the timer TM2, and the reagent (pH adjusting solution) in the container Y ₄ is supplied to PS51 and PS52.
At the same time, the solenoid valve V4 is controlled so as to be charged into the reaction vessel 11 only when the valves are turned on. It is provided an electromagnetic valve V2, V3 for controlling the opening and closing in the piping of the vessel Y _1, Y _4.

Each of the containers Y ₁ , Y ₂ , Y ₃ and Y ₄ is provided with a liquid inlet I ₁ , I ₂ , I ₃ and I ₄ having a sealing lid, and a constant pressure is applied to each container. Add tube line 31
And a tube line 32 for constant decompression. As shown in FIG. 2, a constant pressure is introduced into the tube line 31 through a line A ′ connected to an air pump AP via a pressure reducing valve PR to introduce a constant pressure to each container Y ₁
To Y ₄ apply a constant pressure. A vacuum pump VP is connected to the tube line 32 by a line V as shown in FIG. 3, and the vacuum pump VP is also connected to a waste liquid container D. Further, the air pump AP and the vacuum pump VP are connected to the reaction container 11 via the external extraction container B and the lines A and V, respectively.

Each of the containers Y ₁ to Y ₄ has a solenoid valve V ₁ to
From closed to inlet I ₁ ~I ₄ of V _4, was charged with each reagent or solvent and is sealed by a lid after turning.

In FIG. 1, Me is a storage container for a cleaning solvent such as methanol, and H is a storage container for a cleaning solvent such as water. These containers Me and H are connected to the tube line 31 via a solenoid valve. is doing.

When a constant pressure is applied to each container from the pressure tube line 31, the liquid in the container Y ₁ is introduced into the reaction container 11 when the electromagnetic valve V ₁ is opened. After completion of the reaction, for example, when the electromagnetic valve V ₁ is closed, the container Y ₁ is depressurized with a constant vacuum, the cleaning solvent (Me or H) is selected, and the required cleaning liquid is injected into the container Y _1. Can be done. The same applies to other containers.

The liquid in the containers Y ₁ and Y ₄ is introduced into the reaction container 11 by a pair of timers TM provided in each pipe.
1, TM2 when open solenoid valves V _1, V ₄ by, the solenoid valve V _1,
By opening and closing V _{4 according} to the time chart of timers TM1 and TM2 shown in FIG. 5, the liquids in the containers Y ₁ and Y ₄ are simultaneously dropped into the reaction container 11 at regular intervals.

In FIG. 5, intervals of about 5 seconds (time T
0) shows a time chart in the case of dropping. Twin timer (TM1 and TM2 are OMRON H3B
Switch PS12, PS5 at the same time of turning on (using F-8)
2 is turned on and PS12 and PS52 turn off after T0 hours. However, the twin timer output switch PS1
1 and PS51 are turned on for a short time respectively set and turned off immediately (having a function of one-shot multivibrator), the solenoid valves V1 and V4 are operated only for this limited time, and the container Y ₁ added dropwise by an amount exactly the liquid Y _4. Since the liquid is pushed out at a constant pressure even if the amount of the liquid changes, it is possible to surely drop the two liquids simultaneously. When the dropping method is used, the amount of one dropping can be controlled even during the dropping operation by finely adjusting the set time (on time) of the twin timer dial. This function is the same as the experimenter's fine adjustment of the cock. Incidentally, container Y ₁
If only one liquid is to be dropped, only the switch PS12 may be cut off.

Outside the reaction container 11 and the heat medium container 12
The inside gap of the heat medium is used as the heat medium flow passage, and the heat medium container 1
A pipe 42 that circulates the heat medium is connected between the pair of ports 13 and 14 provided in 2 and the heat medium tank 41 that stores the heat medium. In the heat medium tank 41, one end 42a of the pipe 42 is hung inside the heat medium, and the other end 42b is
Is arranged above the liquid surface of the heat medium, and one end 4 of the pipe 42 is
2a and the port 13 of the heat medium container 12 between the pump P1
The heat medium is introduced from the heat medium tank 41 through the port 13 into the heat medium container 12 and circulated in the heat medium tank 41 through the pipe 42 from the port 14.

In this embodiment, silicon oil of -20.degree. C. is used as the heat medium for accumulating in the heat medium tank 41 and circulating the pipe 42, and the cooling medium is used as the heat medium. This cooling medium is supplied to the heating medium container 11 as described later.
The heating medium is heated by a heater 19 installed inside the heating medium to control the temperature of the heating medium in the heating medium container to a required temperature.

Therefore, when the temperature of the liquid inside the reaction vessel 11 rapidly rises due to the heat of reaction and the temperature of the heat medium in the heat medium vessel 12 is to be rapidly lowered, the pump P1 is rotated in the reverse direction to generate heat. The heat medium inside the medium container 12 is transferred to the heat medium tank 41.
To the heat medium container 12 by supplying the heat medium in the heat medium tank 41 to the heat medium container 12 by rotating the pump P1 in the forward direction.
The temperature of the heat medium inside the heat medium container 12 can be drastically lowered, and the temperature of the reaction liquid can be rapidly lowered within a predetermined constant range. Furthermore, the pump P1 is reversed to adjust the returning amount of the heat medium from the heat medium container 12 to the heat medium tank 41, so that the liquid level of the heat medium in the heat medium container 12 is adjusted to the level of the solution in the reaction vessel 11. It is possible to adjust the height to the liquid level.

In the figure, 43 is a liquid take-out tube for taking out the liquid inside the reaction vessel 11 to the take-out vessel B via the solenoid valve 44, and 4
Reference numeral 7 is a tube line for taking out the internal gas from the reaction container 11 to the outside through the reflux pipe 45 and the electromagnetic valve 46.

As described above, the liquid in the reaction vessel 11 is
The temperature of the heat medium is controlled by the heater 19 arranged between the outside of the bottom surface of the reaction container 11 and the inside of the bottom surface of the heat medium container 12 so that the temperature is within a certain temperature range. The control system is as shown in FIG. In FIG. 6, TC is a temperature controller, and based on the difference between the temperature detected by the heat medium temperature sensor TC2 and the set temperature instructed by the computer, the temperature of the heat medium and the reaction vessel 1
The heater 19 is turned on or off so that the liquid in 1 reaches a predetermined temperature.

Further, in FIG. 6, IF is an interface (U.S.A. manufactured by Optmax Co., Ltd.) for converting a serial signal serially transmitted from the control computer CPU through the transmission line into a parallel signal. Line P
H is a line connecting the pH sensor PHS and the interface. The pH value of the solution in the reaction vessel 11 is output from the pH sensor through the line PH, and the detected value and the CPU are output.
Based on the difference from the pH value set in
The electromagnetic valve V4 provided in the pipe connecting the reagent container Y ₄ filled with the adjusting liquid and the reaction container 11 is opened and closed to drop the pH adjusting liquid into the reaction container 11 so that the reaction solution has a predetermined pH. Are controlled.

The interface IF is the output line P1 '.
The heat medium circulation pump P1 is operated and controlled by an output signal from the solenoid valve, and each solenoid valve V1 to V is output via the output line EV.
It is connected to the switch No. 4 to control the opening and closing of these solenoid valves. As described above, the temperature sensor TCl hangs down inside the reaction vessel 11 to directly measure the temperature of the liquid and inputs the detected value to the interface. The detected value is C
When it goes out of a certain temperature range preset by PU,
As shown in FIG. 4, the switch PS1 of the solenoid valves V1 and V4
Signals are output from the CPU to 2, 52 and timers TM1 and TM2 to turn off the solenoid valves V1 and V4, and to turn them on when they are within a certain range.

Further, the detection signal from the heat medium temperature sensor TC2 is input to the temperature controller TC, and the heater 19 is operated by the temperature controller TC based on the difference between the detected value and the preset value input to the CPU. hand,
The temperature of the heat medium is controlled to fall within the required range, and the temperature of the solution in the reaction vessel 11 is controlled to fall within the required range by controlling the temperature of the heat medium. Alternatively, the heat medium temperature is gradually raised as necessary.

Specifically, for example, when the reaction temperature is controlled at 5 to 10 ° C., the silicon liquid stored in the heat medium tank 41 is cooled to −20 ° C. by the action of the cooler 50. The heat medium at -20 ° C. is supplied to the reaction vessel 11 by the pump P1
It is fed into the gap between the heating medium container 12 and the heating medium container 12, and is locally heated by the heater 19 to control the temperature of the liquid in the reaction container 11 to the set temperature. The heat medium temperature in the heat medium container 12 is detected by the thermocouple of TC2. The temperature of the liquid in the reaction container 11 accompanying the dropping reaction of the reagent is quickly detected by the liquid temperature sensor TC1. When the temperature of the liquid exceeds a certain range set by the heat of reaction generation, that is, when the temperature rises to 10 ° C. or higher in this embodiment, the dropping of the reagent is temporarily stopped. Therefore, the liquid temperature in the reaction vessel is automatically cooled to near the set temperature (5 ° C.) by circulating the heat medium made of cooled silicon. Therefore, the temperature range of 5 to 10 ° C. can be maintained. Conversely, set the temperature of the liquid in the reaction vessel to room temperature.
When it is necessary to raise the temperature (about 25 ° C.) or more, since the cooling silicon is constantly circulated and the heat capacity of the heater 19 is small, the temperature rise does not occur. Therefore, the pump P1 is stopped and the cooling silicon is circulated. Is stopped and the local heater 19 is used to heat the temperature. The temperature sensor TC2 detects the temperature so that it becomes a predetermined temperature, and the temperature controller TC controls the temperature. During the temperature control, the solution and the heat medium in the reaction vessel 11 are constantly stirred and rotated so that the temperature unevenness does not occur.

[0044]

[Experimental Example 1] A case of synthesizing ethyl benzoylacetate using the automatic synthesizer of the present invention will be described. This synthesis is described in the literature; Organic synthes [Organic synthes
is, col, vol., IV, 415 (1963)],
The reaction formula is as shown in the following reaction formula 1.

[0045]

[Chemical 1]

The above reaction formula is obtained by the following reaction steps. Above 1 (19.5g), water (50ml), hexane (25m
The solution of l) is put into a reaction vessel and the temperature is controlled at 5 ° C.
Then, 33% of the above 3 was dropped into the reaction vessel and the temperature was adjusted to 1
The temperature is controlled to 0 ° C. or lower and pH 11 or lower. Then, with vigorous stirring, under the temperature condition of 10 ° C or less, the above 2 (23
g), 33% of the above 3 (27 ml) is added dropwise to the reaction vessel.
This dropping is performed by simultaneous dropping over 2 hours. After the dropping is completed, the temperature is naturally raised to room temperature and then to 35 ° C. over 1 hour. Then, the stirring is stopped, and liquid separation is performed to remove the organic layer. Then 5 (8.0 g) above was added dropwise and slowly stirred overnight. Then, after adding NaCl (9.0 g), liquid separation was carried out, the aqueous layer was removed, cold water washing (10 ml) was carried out 3 times, concentration and distillation were carried out to obtain the final product ethyl benzoyl acetate.

An experimental example in which the above-mentioned reaction step is carried out by the above-mentioned automatic synthesis reactor according to the present invention will be described in detail below. The synthetic operation procedure consists of the following 18 steps.

1) Read the synthesis program (semi-automatic program execution). The reaction vessel 11 is cooled to 5 ° C. 2) Ethyl acetoacetate ( 1 ): 19.1 ml, water: 50.0 m
l, Hexane: 25.0 ml is put in the reaction vessel 11 and stirred. 3) Add benzoyl chloride ( 2 ): 19.1 ml to the reagent container Y ₁ . 4) 33% aqueous sodium hydroxide ( 3 ) solution: 39.5 ml is placed in the reagent container Y ₄ . 5) Switch to the automatic synthesis program and execute it.・ ・
... Start automatic synthesis operation. Dropping: 33% aqueous sodium hydroxide solution in container Y ₄ is dropped. The solenoid valve V4 is automatically controlled to automatically adjust the pH to 11, and the temperature of 5 to 10 ° C is maintained. When the pH reaches 11, the simultaneous dropping of the two liquids in the containers Y ₁ and Y ₄ is started (twin timers TM1 and TM2). The reaction temperature is kept at 5-10 ° C. (When the reaction temperature exceeds 10 ° C, the dropping of the two liquids is stopped and cooled.) When the pH value becomes 10.8 or less, benzoyl chloride ( 2 )
The dripping is suspended, and only 33% aqueous sodium hydroxide solution is added (starting dripping of one liquid). When the pH becomes 10.8 or higher, simultaneous dropping is restarted. When all the benzoyl chloride enters the reaction vessel and the pH exceeds 11.3, the reaction ends. Automatic temperature rise: Stop the cooling silicon circulation pump P1 and turn to 5
It takes 1.5 hours to automatically raise the temperature from ℃ to 35 ℃. 6) Stop stirring and switch from the automatic synthesis program to the semi-automatic program. The solution in the reaction container 11 is moved to the container B. 7) Separation: Only the lower aqueous layer is moved to the reaction vessel 11, and the organic layer is discarded. 8) Ammonium chloride (crystal): 8.0 g in a reaction vessel 11
And slowly stir overnight. 9) NaCl: 9.0 g is put in the reaction vessel 11 and stirred. The product in the reaction vessel 11 is moved to the vessel B and transferred from the vessel B to a separating funnel C (not shown). 10) Separation: The lower aqueous layer is discarded, and the upper layer is left in the separating funnel C. 11) Dichloromethane (about 15 ml) is put into the reaction vessel 11 and rinsed, and this solution is moved to the vessel B. The container B is put into the rinsing separating funnel C (collection). 12) Washing with water: Add 10 ml of cold water to a separating funnel. 13) Separation: Separation is performed, the lower layer is placed in a container E (not shown), and the upper layer (water layer) is discarded. The lower layer is transferred to a separating funnel C. 14) 12) Washing with water and 13) Separation are repeated 3 times. 15) Concentration: The product in the container E is concentrated (40 ° C., about 30 minutes) by a rotary evaporator. 16) Distillation: Distill at 130 ° C and 8 mmHg with a distillation apparatus
(Rotary pump, trap-70 ° C). Initial distillation temperature 40
The purified product is collected by switching at around 90 ° C and 90 ° C. 17) Final product 6 : ethyl benzoyl acetate is obtained. 18) Washing and drying: The equipment is automatically washed.

7 to 12 are control flowcharts of the step of the above-mentioned automatic synthesizing operation 5). FIG. 7 shows an outline of the entire control flow chart. S1 to S3 show the steps 4), V and S5 are steps 5), W and S7 are steps 5), and S8 and Y are steps 5). Details of V, W, and Y are shown in FIGS. 8 to 12, respectively.

Step S1 of FIG. 7 is an initial set, which is the initialization of the apparatus, that is, the reaction vessel 11 is charged with the above ethyl acetoacetate, water and hexane, and the reagent vessel Y ₁ is benzoyl chloride and Y ₄ is 33% water. An aqueous solution of sodium oxide is charged, the stirrer 21 is turned on, the cooler of the heat medium tank 41 is operated to cool the silicon oil, and the pump P1 is driven to circulate the silicon to the heat medium container 12 for cooling operation. Start, cool reaction vessel 11 to 5 ° C.,
Also, the interface is initialized.

The screen 1 of S2 is a screen display and a reaction formula display,
Display the temperature. Is preparation for synthesis good for S3?
Has it reached 5 ° C? To confirm.

Dropping of one liquid of V was carried out at a temperature of 5 to 10 ° C. in a container Y ₄
Of aqueous sodium hydroxide solution is added dropwise. (At this point, heat is generated.) The pH of S5 is controlled to be 11 or more by dropping the aqueous solution of sodium hydroxide, and the pH of S5> = 11? Confirms that the pH value has reached 11.0. 10 drops of W liquid
Simultaneous dropping is carried out while maintaining the pH at 10.5 to 10.8 at ℃ or less. (The temperature controller works so that the temperature does not drop below the set temperature (5 ℃).)

At S7 (pH => 11.3), the pH value is 1
Check if it has become 1.3. P1 OFF of S8 is stopped because the temperature of the cooling circulation pump P1 is raised. As for the automatic temperature increase of Y, the automatic temperature increase is performed from 5 ° C to 35 ° C in 90 minutes.

As shown in the above step, if preparation for synthesis is good, dropping of one liquid of the pH adjusting liquid starts at a temperature of 5 to 10 ° C., and when the pH value becomes 11.0 (set value), the reaction Drip of the two liquids of the reagent and the pH adjusting liquid starts. Keeping the temperature of the reaction solution (within the set value) within 5-10 ° C for the dropping of these two liquids,
In addition, the pH is maintained at 11 or more. All of the benzoyl chloride is put into the reaction vessel 11, and when the pH becomes 11.3, the automatic temperature rise starts.

FIG. 8 shows details of the step of dropping one droplet of the pH adjusting liquid of V (sodium hydroxide aqueous solution). V
In 1, the solution temperature is measured by the solution temperature sensor. V2
Check if the temperature is 10 ° C or less. If NO, use V3 to set the solenoid valve V
4 is turned off and the dropping is not carried out. Instead, V4 is displayed and the temperature of V1 is measured again. When the temperature is 10 ° C. or lower, Y ₄ is dropped, pH is measured at V5, and displayed at V6. V
When pH <= 11.0 in 7 and pH is 11.0 or less, V8 keeps dropping while controlling the valve opening time of the solenoid valve V4 by V8, and when pH becomes 11 or more, V9
Then, the solenoid valve V4 is turned off to stop the dropping of the sodium hydroxide aqueous solution.

FIG. 9 shows benzoyl chloride, Y ₄ from container Y ₁ .
3 shows in detail the step of simultaneously dropping the aqueous sodium hydroxide solution from the above. The temperature of the solution in the reaction container 11 is measured by the liquid temperature sensor at W1 while the two liquids are simultaneously dropped from the containers Y ₁ and Y ₄ . The pH of the solution is measured with a pH sensor at W2. If the temperature is 10 ° C. or lower at W3 and the answer is NO, then at W4 both solenoid valves V1 and V4 are turned off to stop the dropping of the two liquids, and the display at W5 waits for cooling. If the temperature is 10 ° C. or lower in W3, the two liquids are simultaneously dropped in W6. Measure pH with W7. W8 p
Confirm that H> 10.5, and if the pH is 10.5 or less, turn off the solenoid valve V1 at W9, temporarily stop the addition of benzoyl chloride, and at W10, from solution Y ₄ to a solution of sodium hydroxide alone. Add dropwise to raise the pH. PH <= with W11
Check 10.8. If the pH is above 10.8, W1
The simultaneous dropping of the two liquids is restarted at 5. If the pH is above 10.8, the W12 delay will wait for about 5 seconds. W
At 13, the photo sensor PS1 detects the liquid in the Y ₁ container. When there is no more liquid to be detected by the photosensor PS1, PS1 = 1, and it is confirmed at W14 whether PS1 = 1. When PS1 = 1, W17 turns off the solenoid valve V1.
Then, one liquid was dropped from Y _{4 at} W18, and then W1
Measure pH at 9 and confirm pH => 11.3 at W20. If NO, the process returns to W18 again, and if YES, the process ends.

FIG. 10 shows timer dropping. At VT1, a timer TM2 connected to the solenoid valve V4 of the container Y ₄ is turned on. The solenoid valve V4 is turned on at VT2. Delay with VT3 (waiting time about 5 seconds). The solenoid valve V4 is turned off at VT4.
Turn off the timer TM2 at VT5. Delay with VT6 (wait time about 5 seconds).

FIG. 11 shows the control of the timer for simultaneous dropping of W15. Turn on timers TM1 and TM2 at WT1. Turn on solenoid valves V1 and V4 at WT2. Delay with WT3 (wait time about 5 seconds). Turn off solenoid valves V1 and V4 at WT4. Turn off timers TM1 and TM2 at WT5. W
Delay at T6 (wait time about 5 seconds). The time for turning on the twin timer can be set on the dial scale. The discharge time of the solution is synchronized with the opening time of V1 and V4, and is only a very short time ΔT ₁ and ΔT ₂ set by the twin timer. In addition, each twin timer setting time
By changing the time to T ₁ 'and ΔT ₂ ', fine adjustment of the dropping amount becomes possible.

FIG. 12 shows details of the automatic temperature increase Y. Y ₁
In the process, TC1 = 5 and the start temperature is set to 5 ° C. In Y ₂ , TS = TC1. TC1 is a counter. Send the set temperature (TS) with Y ₃ and send the set value to the temperature controller. The temperature controller detects the temperature with the temperature sensor TS2. The electric power is controlled by the heater so that there is no difference from the set temperature. Delay 3 with Y ₄
Wait 3 minutes as a minute. TC1 = TC1 + 1 for Y ₅
And TC6 ≧ 35 for Y ₆ ? Check that the temperature has reached 35 ° C. In this example, the temperature was raised from 5 ° C to 35 ° C in 90 minutes after the reaction was completed. TC1 is 5 ℃, the final temperature is 3
It is 5 °. Increase the set temperature by + 1 ° C every 3 minutes. The command of the set temperature is issued to the temperature controller via the communication line (RS232C). The mechanism of temperature control is shown in FIG. Turn off the circulation pump before raising the temperature.

In Experimental Example 1 which was carried out in the synthetic reaction operation procedure based on the control mode shown in the above flow chart, the final product ethyl benzoyl acetate was 20.20 g.
It could be obtained and the yield was 70.1%. It should be noted that the highest yield is 68% when an expert experimenter performs the above synthetic reaction operation without using the automatic synthetic reaction apparatus of the present invention (due to the above literature). As described above, in the present apparatus, while adjusting the temperature and pH of the solution in the reaction vessel, the two liquids were automatically dropped when the temperature and the pH were within a certain range, so that an experiment expert could be used. It was not necessary, and the yield could be increased higher than the operation by an expert.

[0061]

[Experimental Example 2] Using the automatic synthesis reactor according to the present invention,
N-Benzylcarbamate ethyl was synthesized. This synthesis is described in the literature; Organic synthesis [Organicin synt
hes-is col.vol., N, 780 (1963)],
The reaction formula is as shown in the following reaction formula 2.

[0062]

[Chemical 2]

The above reaction formula is conventionally obtained by the following reaction steps. Under ice-cooling, the above 1 (25 g), ice water (12.5 ml) and crushed ice (37.5 g) were mixed, and the above 2 (13.
125 g) is added dropwise while keeping the reaction temperature at 10 to 15 ° C (it takes 1 to 1.5 hours). Then water (12.5 ml) and crushed ice (25 g) are added. Then, above 2 (13.13)
g) and an aqueous sodium hydroxide solution (10 g of water 32.
(Solution dissolved in 5 ml) is added at the same time, and the solution temperature is 10-
Add dropwise while maintaining at 15 ° C (requires 2.5 to 3 hours).
Further, after stirring for 30 minutes, the precipitate is collected by filtration, washed with a sufficient amount of cold water, and then air-dried to obtain crystals.

The above-mentioned reaction steps were carried out by the automatic synthesis reaction apparatus of the present invention. Since this apparatus has an excellent cooling capacity, the synthesis was carried out by the following method without using ice. The reaction vessel 11 is cooled by the circulation of a cooling medium consisting of cooling silicon oil, in a state cooled to 2 ° C., the reaction vessel 11 above 1 (2
5.5 ml) and water (50 ml) were added. Then, while maintaining the temperature at 2 to 5 ° C., one drop of the above 2 (11.9 ml) was dropped from the container Y ₁ (1 hour). After that, while maintaining the temperature at 2 to 5 ° C., the above-mentioned 2 (11.9 ml) from the container Y ₁ and the pH from the container Y ₄
33% aqueous sodium hydroxide solution (32.5 ml) was added dropwise so as to maintain the ratio of 5 to 7 and the two liquids were added simultaneously (1.5.
time). Then, the mixture was stirred for 30 minutes, filtered, washed with water, and dried to obtain crystals.

The results of the synthesis of ethyl N-benzicarbamate are shown in Table 1 below.

[0066]

[Table 1]

In Experimental Example 2, when the pH value was not controlled, 2 out of 3 samples did not crystallize and remained in a droplet state. Then, when the reaction was carried out while maintaining the pH value in the range of 5 to 7 as described above, crystals could be obtained. From the results, it was found that pH control is an important factor during the reaction.

[0068]

[Experimental Example 3] Using the automatic synthesis reactor according to the present invention,
Diethyl hydrazodicarboxylate was synthesized. This synthesis is described in the literature; Organic synthesis [Organic syn
the-sis col.vol., VI, 411 (1963)],
The reaction formula is as shown in the following reaction formula 3.

[0069]

[Chemical 3]

The above reaction formula is conventionally obtained by the following reaction steps. Hydrazine hydrate 1 (7.5 g) and 95% ethanol (75 ml) were stirred and ethyl chlorocarbonate 2 (16.3 g) was added dropwise to the reaction vessel cooled to 10 ° C., and the solution temperature was adjusted to 1
The reaction was carried out while maintaining the temperature at 5 to 20 ° C, and when the whole amount of the solution had been added, the above 2 and sodium carbonate 3 (15.9 g) water (75 ml) were added.
Is added at the same time, and when the addition is completed, the above 2 is added so as to be slightly faster. After finishing the dropping, wash the inside of the container with water (20 ml) and stir for 30 minutes. The precipitate is collected by filtration, washed with 1000 ml of cold water, and dried under reduced pressure at 80 ° C. to obtain crystals of final product 4 .

The above reaction process was performed by the apparatus of the present invention.
The amount of each reagent and solvent was the same as the conventional amount. Reaction vessel 1
The above 1 and 95% ethanol were put in 1 and the reaction vessel 11 was cooled to 10 ° C. by circulating a heat medium, and then 15 to 20 ° C.
The above 2 was dropped from the container Y ₁ while adjusting to the range. Then, while adjusting the temperature to 20 ° C. or lower, the same amount of the above reagent 2 was dropped from the container Y _{1 at} the same time from the container Y ₄ together with the above 3 and water to obtain the above crystal of 4 .

The crystal of the above 4 was 19.08 g, which was 1.1 from the mother liquor.
A total of 20.96 g of crystals, 88 g, was obtained with a yield of 79.4%.
Met. The results of synthesis are shown in Table 2 below.

[0073]

[Table 2]

In Experimental Example 3 described above, the reaction could be easily performed by controlling the temperature of the reaction solution within a predetermined range and dropping the reagent within the temperature range. In Experimental Example 3, the pH was not adjusted.

[0075]

As is apparent from the above description, according to the present invention, a temperature sensor is arranged in the reaction container to directly measure the temperature of the liquid, and the reagent is dropped from the reagent container based on the detection value from the sensor. The temperature of the heat medium is controlled in accordance with the detected value from the liquid temperature sensor or the heat medium temperature sensor, so that the reagent can be dropped while keeping the liquid temperature in the reaction vessel within the required range. It can be done and reacted.

In addition, a pH sensor is arranged in the reaction container, and a pH adjusting liquid is dropped into the reaction container according to a detection value from the pH sensor to adjust the pH to a predetermined constant range. Therefore, it can be effectively used at the time of synthesis in which it is necessary to drop a reagent to cause a reaction when the pH and temperature of the liquid in the reaction container are within a certain range.

Further, a plurality of reagent containers are connected to the reaction container via piping, and an opening / closing valve composed of an electromagnetic valve is provided in the piping to open / close at a constant time interval at the same timing according to a command from the CPU. At the same time, since the solution is dropped under a constant pressure, it is possible to always cause the reaction by dropping the two liquids at a constant rate and under a constant condition with high accuracy. Furthermore, the opening time of the solenoid valve is controlled by a timer, and
Since the timer can be adjusted by manual operation, fine adjustment of the dropping amount can be easily performed.

For example, the automatic synthesis reaction apparatus according to the present invention and CONTRAVE used by Codex Co.
Compared to the S automatic synthesizer, the latter adjusts the height of the heat medium to the height of the reaction liquid, controls simultaneous dropping of two liquids, temperature, pH, simultaneous dropping, changes in dropping amount during automatic dropping, automatic washing The former has the advantage of being able to perform all of the above-mentioned functions, in contrast to the fact that the functions (reagents, reaction vessels) are disabled and only automatic temperature rise is possible.

[Brief description of drawings]

FIG. 1 is a schematic configuration diagram of an automatic synthesis reaction device of the present invention.

FIG. 2 is a circuit diagram of an air pump that drives the apparatus of FIG.

FIG. 3 is a circuit diagram of a vacuum pump that drives the apparatus of FIG.

4 is an electric circuit diagram of a timer of the apparatus of FIG.

5 is a signal waveform diagram of the circuit of FIG.

6 is a system diagram of temperature control of the apparatus of FIG.

FIG. 7 is a control flowchart of the apparatus shown in FIG.

8 is a flow chart diagram for one drop of FIG. 7. FIG.

FIG. 9 is a flow chart diagram of the timer for two drops below in FIG. 7.

10 is a flowchart of the timer dropping in FIG.

FIG. 11 is a flow chart of simultaneous dropping of FIG.

FIG. 12 is a flow chart of the automatic temperature rise of FIG.

[Explanation of symbols]

11 Reaction Container 12 Heat Medium Container 15 Lid 17 Stirrer 20 Spinner 21 Magnetic Stirrer 41 Heat Medium Tank 42 Piping B External Container M Washing Solvent Container (Methanol) H Washing Solvent Container (Water) D Waste Liquid Container TC1 Liquid Temperature Sensor TC2 Heat medium temperature sensor PHS pH sensor V1, V2, V3, V4 solenoid valve TM1, TM2 timer _{Y 1, Y 2, Y 3} , Y 4 container AP air pump PR pressure reducing valve VP vacuum pump IF interface PS1~PS5 photosensor V vacuum line Connect to trap A Connect to air pump L leak (Open)

Claims (7)

[Claims] 1. A reaction container surrounded by a heat medium container is automatically supplied with a reagent from a reagent container through a pipe, and a synthetic reaction is carried out. A liquid temperature sensor is provided in the reaction container. On the other hand, while providing an on-off valve in the pipe, a temperature control means for the heat medium to be inserted between the heat medium container and the reaction vessel is provided, and the on-off valve and the temperature control means are provided from the liquid temperature sensor. Control for operating the liquid temperature in the reaction container within a predetermined constant range and operating the on-off valve so as to supply the reagent into the reaction container within the predetermined temperature range. An automatic synthesis reactor characterized by having a circuit. 2. A reaction container surrounded by a heat medium container is automatically supplied with a reagent from a reagent container through a pipe to perform a synthetic reaction, and a liquid temperature sensor is provided in the reaction container. A heat medium temperature sensor is provided between the heat medium container and the reaction container while providing an opening / closing valve in the pipe, and means for controlling the temperature of the heat medium is provided. The liquid temperature in the reaction vessel is controlled within a predetermined constant range by operating the heat medium temperature control means in response to the detection signal from the liquid temperature sensor, and the liquid temperature is within the predetermined range according to the detection signal from the liquid temperature sensor. An automatic synthesis reaction apparatus is provided with a control circuit for operating the on-off valve so as to supply a reagent into the reaction container at the time. 3. A pH sensor is provided in the reaction container, and at least one of the reagent containers connected to the reaction container through a pipe is a container for a pH adjusting reagent, and the control circuit includes a pH sensor. The above-mentioned on-off valve is operated so that the pH is within a predetermined constant range in accordance with the detection signal of, and the pH adjusting liquid is supplied to the reaction container, and the liquid temperature and pH in the reaction container are within the predetermined constant range. The automatic synthesis reaction apparatus according to claim 1, wherein the reagent is controlled so as to supply the reagent from another reagent container to the reaction container at times. 4. The solenoid valve is used as the opening / closing valve, and a timer for operating the solenoid valve is provided so that the solenoid valve is opened for a required time set by the timer in response to an operation signal from the control circuit. The automatic synthesis reactor according to claim 1. 5. The automatic synthesis reaction apparatus according to claim 4, wherein the set time by the timer is manually operable. 6. The reaction container is connected to a plurality of reagent containers via pipes each provided with a solenoid valve, and a timer is connected to each solenoid valve, and the control circuit uses the timer to connect the solenoid valves. Open and close at the same timing at a fixed time interval, and turn on and off the timer with the detection signals of the liquid temperature sensor and pH sensor to turn on and off the temperature and pH of the solution in the reaction vessel.
6. The automatic synthesis reaction apparatus according to any one of claims 4 and 5, wherein two or more reagents are simultaneously supplied from a reagent container when is within a required fixed range. 7. The automatic synthesis reaction apparatus according to claim 1, wherein the reagent is supplied from the reagent container to the reaction container by dropping while supplying a constant pressure.