APPARATUS AND METHOD FOR SYNTHESIZING A VARIETY OF CHEMICAL COMPOUNDS IN A SINGLE BATCH.

FIELD OF THE INVENTION The invention relates to an improved apparatus and method for automatically synthesizing a variety of chemical compounds and a method therefor and more particularly to an automated apparatus and method capable of simultaneously synthesizing a number of chemical compounds in a reaction container in a reduced period of time.

BACKGROUND OF THE INVENTION

Among others, Japanese Laid-Open Publications Nos. 2-2870 and 5-192563, filed by the present applicant, disclose devices for use with a computer to automatically synthesize a chemical compound. Each of these automated synthesizing devices performs a plurality of sequential processes, i.e., adding a chemical reagent, heating, cooling, stirring, condensing, extracting, pH controlling, reaction tracing (analyzing) , refining, and rinsing, thereby synthesizing only one chemical compound.

Specifically, a single chemical reaction is performed in a reaction container to synthesize a chemical compound. The chemical compound is then transported to

another reaction container where an after-treatment is provided therewith to eventually synthesize a desired chemical compound. Subsequently, the resulting chemical compound is analyzed and then refined. When developing a new medicine using such automated synthesizing device, one chemical compound expected to have a certain medical effect is synthesized and then its chemical feature is confirmed. If it is determined by subsequent tests that the synthesized chemical compound has the desired medical effect, a number of chemical compounds are further synthesized one by one using the device for seeking other chemical compounds having the same and greater medical effect.

Incidentally, it is to be understood that a new medicine can luckily be developed or found in an enormous number of chemical compounds synthesized. Therefore, the automated synthesizing device can certainly be a good tool for saving both labor and time in synthesizing such number of chemical compounds than synthesizing them through manual operations. However, -because the device is to produce one chemical compound through one reaction, it still needs significant labor and time for synthesizing such great number of compounds, which causes the development of new medicine costly.

SUMMARY OF THE INVENTION

Among the several objects of this invention may

be noted the provision of an improved synthesizing apparatus and method for simultaneously synthesizing a variety of chemical compounds, thereby capable of developing a new medicine efficiently and inexpensively. To this end, the automated synthesizing apparatus of the invention has a plurality of material receptacles each of which accommodating a liquid material, a first reaction chamber, a first supply means which communicates the material receptacles with the first reaction chamber to supply the materials to the first reaction chamber, and a controller which controls the first supply means so that a plurality of materials are selected and then supplied to the first reaction container where the selected materials are simultaneously react to synthesize a plurality of compounds.

It should be noted that the invention can be applied to a similar automated synthesizing device disclosed in Japanese Patent Laid-Open Publication No. 7- 13058 filed by the applicant. The material may be a single material or a mixture of a plurality of liquid materials.

In another aspect of the invention, the synthesizing device includes a second reaction chamber for providing an after-treatment for the compounds synthesized in the first reaction chamber and a transporting means which communicates between the first and second reaction chambers for transporting the compounds from the first

reaction chamber to the second reaction chamber and vice versa. The controller causes the material receptacle to supply the material to the first reaction chamber to react the supplied material with the compounds transported from the second reaction chamber.

The first and second reaction chambers may be contained in a reaction unit.

According to the automated synthesizing device of the invention, a plurality of chemical compounds can be synthesized through each reactions, although the prior art synthesizing device can synthesize only one compound through each reactions. For example, by supplying one basic material and three other mixing materials to the reacting chamber and then reacting them, three compounds are synthesized simultaneously. Further, by supplying three other materials to the reacting chamber and then react them with the firstly synthesized three compounds, nine compounds are synthesized. Furthermore, by supplying three other materials to the reacting chamber and then react them with the synthesized nine compounds, twenty- seven compounds are synthesized. Thus, a synthesizing rate is accelerated exponentially by repeating the reactions. In this instance, even if a synthesizing scale for one reaction is limited to 500mg, when the three reactions has finished, each of twenty-seven compounds has a weight of about 20mg, which is sufficient for a subsequent screening. The synthesizing device may includes a plurality

of reagent receptacles each of the reagent receptacle accommodating a reagent, a plurality of solvent receptacles each of said solvent receptacle accommodating a solvent, and a second supply means which communicates between the reagent and solvent receptacles and the first and second reaction chambers for supplying the reagent and/or solvent to the first and/or second reaction chamber, and the controller may control the second supply means.

Each of the material receptacles may accommodate a certain amount of one or more materials to be used in one reaction in the reaction chamber. In this instance, it is not necessary to provide the device with a measuring means for measuring the material to be fed from the material receptacle, which simplifies the structure of the device and possibly reduces the loss of the expensive material.

The first supply means may include a common tube one end thereof being connected with the first reaction chamber, a plurality of branch tubes each of the branch tube being connected at one end thereof with the material receptacle and at the other end thereof with the other end of the common tube, and a measuring means arranged in the common tube for measuring the material that flows in the common tube and then feeding the measured material to the first reaction chamber. As the measuring means, a measuring device disclosed in Japanese Patent Laid-Open Publication No. 7-265833 is preferably employed.

With thiε measuring means, each material

receptacle can accommodate a large amount of material in advance. This eliminates frequent charging of the material which would otherwise occurred if the receptacle can accommodate only a small amount of material, thereby renders the synthesizing operations efficient. Further, the same material can be repeatedly supplied and also be supplied to the synthesized compound for further synthesizing therewith. Furthermore, the controller is allowed to freely change the combination of the materials. Preferably, the common tube is connected with the plurality of branch tubes through a rotary valve. In this instance, each material can be measured accurately and then transported from the material receptacles to the reaction chamber in an certain constant time, which simplifies a control program for controlling the automated synthesizing.

The synthesizing device may include a reaction control unit for controlling conditions (for example, temperature) of the reaction performed in the firεt or second reaction chamber. In this instance, the reaction conditions can be controlled precisely.

Further, the synthesizing device may include an analyzing unit (for example, analyzing unit according to a chromatography process) for analyzing the compound synthesized in the first or second reaction chamber. Furthermore, the synthesizing device may include a refining unit for removing impurities from the compound synthesized in the first or second reaction chamber.

Moreover, the refining unit may include a fraction collector. The synthesized compounds may be divided for several containers of this fraction collector and then transported to the reaction chamber where they are reacted with other materials or reagent, thereby further compounds can be synthesized.

A method for simultaneously synthesizing at least one variety of chemical compounds which uses a plurality of receptacles each of which accommodating a material, a reaction chambers, and a transporting means for transporting the material to the reaction chamber includes a step for selecting a plurality of materials and then transporting the selected materials to the reaction chamber, a step for reacting the selected materials in the reaction chamber to produce a plurality of compound, and a step for repeating the above steps to synthesize a number of compounds in the reaction chamber.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects and features of the present invention will become clear from the following description taken in conjunction with the preferred embodiments thereof with reference to the accompanying drawings throughout which like parts are designated by like reference numerals, and in which: Fig. 1 is a schematic block diagram of an automated synthesizing device of the invention;

Fig. 2 is a schematic diagram of a material supply unit incorporated in the automated synthesizing device of the firεt embodiment of the invention;

Figs. 3A and 3B are schematic diagrams showing respective portions of the automated synthesizing device of the first embodiment;

Fig. 4 is a vertical sectional view of a reaction bath for controlling a temperature of a reaction flask in the first embodiment; Fig. 5 is a schematic diagram of the material supply unit of the second embodiment;

Fig. 6 is a vertical sectional view of a measuring pump incorporated in the second embodiment;

Fig. 7 is a schematic diagram of the material supply unit of the third embodiment;

Figs. 8A and 8B are schematic diagrams showing respective portions of the automated synthesizing device of the fourth embodiment;

Figs. 9A and 9B schematic diagrams showing respective portions of the automated synthesizing device of the fifth embodiment;

Fig. 10 is a side elevational view of a sample exchanger incorporated in the fifth embodiment; and

Fig. 11 is a plan view of the sample exchanger.

PREFERRED EMBODIMENT OF THE INVENTION

Firstly, with reference to the drawings, and more

particularly to Fig. 1, a general structure of an automated synthesizing device of the invention and its operation will be described. The automated synthesizing device generally includes a material supply unit (I) , a reaction unit (II) , a reagent/solvent supply unit (III) , a reaction control unit (a temperature control unit) (IV) , an extract/dry unit (V) , an analyze unit (VI) , a refine unit (VII) , a rinse unit (VIII) , a pH control unit (IX) , and a controller, or computer 5, for controlling such units. Preferably, these units and computers are integrally accommodated in a housing not shown.

The material supply unit (I) has a plurality of receptacles (CR) , each of which accommodates a liquid material required for a chemical reaction to be performed. A plurality of materials are measured by a measuring means, or measuring pump 150, and then transported to the reaction unit (II) . The reaction unit (II) includes a first reaction chamber (10) , or flask, for a chemical reaction and a second reaction chamber (10) , or flask, for an after- treatment. The materials transported from the material receptacles (CR) are accommodated in the first reaction chamber (10) . The reagent/solvent supply unit (III) includes a plurality of receptacles (RR) for accommodating respective chemical reagents therein and a plurality of receptacles (RS) for accommodating respective solvents therein. The required chemical reagents and solvents are fed to the first reaction chamber (RF1) . In the reaction

chamber (10) , the materials are reacted each other under a certain condition, thereby synthesizing a plurality of chemical compounds. The computer (5) , in which predetermined reaction conditions are input and stored, controls, among other units, the temperature control unit (V) in accordance with the conditions to synthesize the desired chemical compounds. Then the syntheεized chemical compounds are removed from the first reaction chamber (10) to the second reaction chamber (10) where a certain after- treatment is provided for the compounds. Following the after-treatment, the compounds are removed from the second reaction chamber (10) to the first reaction chamber (10) again where they are reacted with other materials fed from the material supply unit (I) under the existence of reagents and solvents supplied from the reagent/solvent supply unit (III) to synthesize other compounds. Therefore, with a repetition of such processes, a great number of new chemical compounds can be synthesized.

For example, in a first reaction, a reference material (A) and three other materials (B) , (C) , and (D) (these three materials do not react each other) are fed from the material supply unit (I) into the first reaction camber (10) . Then, under a certain condition, the material (A) is reacted with other materials (B) , (C) , and (D) . As a result, three different chemical compounds (A+B) , (A+C) , and (A+D) are synthesized. Subsequently, in the second reaction, three other materials (E) , (F) , and (G) (these

three materials do not react each other) are fed from the material supply unit (I) to the first reaction chamber (10) where they are reacted with the synthesized compounds (A+B) , (A+C) , and (A+D) to synthesize nine different chemical compounds, i.e., (A+B+E) , (A+B+F) , (A+B+G) , (A+C+E) , (A+C+F) , (A+C+G) , (A+D+E) , (A+D+F) , and (A+D+G) .

The automated synthesizing device will be described in detail hereinafter. It should be noted that the automated synthesizing device, illustrated in Figs. 2, 3A and 3B, of the invention includes a plurality of flow lines illuεtrated by solid lines for transporting liquids, among others, material, reagent, solvent, and compounds. Also, each of distal ends thereof illustrated with respective characters (a) to (j) on right hand side in Fig. 3A is fluidly communicated with that illustrated with the corresponding character on left hand side in Fig. 3B. Further, the distal end of the flow line illustrated with a character (k) in Fig. 3A is fluidly communicated with that illustrated with the same character in Fig. 2. Preferably these flow lines are made from a teflon tube. The flow lines are suitably connected with a vacuum pump (not shown) so that a vacuum can be introduced therein to transport the desired liquids. Also, distal end of the flow lines illustrated with a character (v) are connected with the vacuum pump while the distal ends of the flow lines illustrated with a character (w) are connected each other.

Each flow line includes one or more magnetic valves controlled by the computer (5) and is illustrated with a circle having a corresponding reference numeral therein in the drawings. The magnetic valve is preferably made of Teflon. Further, in each of magnetic valves, a port illustrated with a black dot is normally closed, a port shown with a black triangle is a common port, and a port shown without any sign is normally opened.

Referring to Fig. 2, the material supply unit (I) has ten receptacles (1), or (CR1) to (CR10) , for accommodating respective liquid materials. In this embodiment, each receptacle (1) accommodates a specific amount of material, all of which being supplied for one chemical reaction in the reaction chamber. The receptacle (1) has an inlet (la) which protrudes from an upper portion of its circumferential wall so that, when all the material has been supplied for one reaction, the same amount of material is recharged therein. Preferably, the inlet (la) is closed by a cap (lb) . The receptacle (1) is fluidly communicated at a central portion of its protruded bottom with one end of an associated branch tube (tlOO) . Opposite ends of the branch tubes (tlOO) are fluidly communicated through respective magnetic valves (V100) to (V109) with a common tube (tlOl) . Further, a downstream end of the common tube (tlOl) is fluidly communicated through magnetic valves (V110) and (Vlll) with the first reaction chamber, or reaction flask

(10) , of the first reacting station (RF1) in the reaction unit (II) which will be described in detail below.

An upstream end of the common tube (tlOl) , on the other hand, is branched at a magnetic valve (V112) into two ways; one way being connected through a measuring tube (MT) , an optical sensor (PS) , and a magnetic valve (V113) with the vacuum pump, the other way being connected with a container (RS) . This container (RS) accommodates the same solvent as that to be used in the reaction so that the common tube (tlOl) can be rinsed therewith.

Further, the receptacles (1) are fluidly communicated at their top portion through branch tubes (tl03) with corresponding magnetic valves (V117) to (V126) , respectively. These magnetic valves are fluidly connected serially through a common tube (tl02) . An upstream end of the common tube (tl02) is connected through magnetic valves

(V114) to (V116) with the container (WS) having a rinsing liquid therein so that each of receptacles (1) can be rinsed with the rinsing liquid fed from the container (WS) . The above described material supply unit (I) supplies the required materials from receptacles (1) selected by the computer (5) . For example, the basic material (A) is fed from the receptacle (CR1) to the reaction flask (10) of the first reacting station (RF1) . Then, other mixing materials (B) , (C) , and (D) accommodated in respective receptacles (CR2) , (CR3), and (CR4) are fed to the same reaction flask (10) of the firεt reacting

station (RFl) . Preferably, these mixing materials are selected so that they can not react each other. Alternatively, a mixture (B+C+D) consisting of the three mixing materials (B) , (C) , and (D) may be accommodated in the receptacle (for example, receptacle (CR2)) and then fed to the reaction flask (10) .

Referring to Fig. 3, the reaction unit (II) includes a first, a second, and a third reacting stations (RFl) , (RF2) , and (RF3) , each of which having a similar structure. The reacting station includes the reaction flask (10) in which a plurality of chemical processes, such as heating, cooling, stirring, and concentration, can be performed. The first reacting station (RFl) is to synthesize a plurality of compounds in the reaction flask (10) as described above. The second and third reacting stations (RF2) and (RF3) are to provide the compounds synthesized in the first reacting station (RFl) with respective after-treatments in their flasks (10) . If necessary, the flask (10) in the third reacting station (RF3) may be used as a pH control device by substituting another flask available for a pH-controlling for the reaction flask.

Referring to Figs. 3A, 3B, and 4, each of the reacting stations (RFl) , (RF2) , and (RF3) includes the reaction flask (10) , a jacketed bath (11) for controlling a temperature of the flask (10) , and a lift (12) for raising and lowering the bath (11) . The flask (10) , which is

preferably made of glass, has a top opening. This opening is sealingly closed by a removable cap (16) .

The cap (16) of the firεt reacting station (RFl) holds a plurality of tubes passing therethrough into the flask (10) ; a supply tube (t4) extended from the chemical reagent/solvent supply unit (III) , a tube (t7) connected both drier tubes (DTI) and a dividing flask (40) in the extract/dry unit (V) , a stirring tube (20) connected with a tube (tlO) , a tube (tl) connected with the vacuum pump, a tube connected with an associated cooling tube, and electrodes of a concentration sensor (30) .

Likewise, the cap (16) of the second reacting station (RF2) holds a supply tube (t5) , a tube (t8) connected both drier tube (DT2) and the dividing flask (40) , the stirring tube (20) , a tube (t2) connected with the vacuum pump, a tube connected with an associated cooling tube, and electrodes of a concentration sensor (30) . Also, the cap (16) of the third reacting station (RF3) holds a supply tube (t6) , a tube (t9) connected both drier tube (DT3) and the dividing flask (40), the stirring tube (20) , a tube (t3) connected with the vacuum pump, a tube connected with an associated cooling tube, and electrodes of a concentration sensor (30) .

Further, the common tube (tlOl) of the material supply unit (I) is inserted through the cap (16) of the first reacting station (RFl) into its flask (10) so that selected materials can be fed from the material supply unit

(I) into the reaction flask (10) of the first reacting station (RFl) .

The stirring tube (20) has a stirring member (21) adjacent its lowermost end. The stirring member (21) is drivingly connected with a drive source such as motor so that it can rotate to stir the chemical materials in the reaction chamber (10) . The stirring tube (20) can be used to suck the synthesized compounds in the reaction chamber (10) . The sucked compounds are then transported through the tubes (tlO) , (til) , or (tl2) connected at the uppermost end of the stirring tube (20) . The stirring tube (20) can also be used to introduce the required liquid through the tube (tlO) , (til) , or (tl2) into the reaction chamber (10) .

As shown in Figs. 3A and 3B, the tube (tlO) connected with the stirring tube (20) in the first reacting station (RFl) is fluidly communicated through a optical sensor (PS6) , and magnetic valves (V67) , (V70) , (V76) , (V77) , (V115), and (V31) with the dividing flask (40) .

The tube (til) connected with the stirring tube (20) in the second reacting station (RF2) is joined through a optical sensor (PS7) , and magnetic valves (V64) , (V72) , (V75) , and (V76) with the tube (tlO) and thereby fluidly communicated with the dividing flask (40) . Likewise, the tube (tl2) connected with the stirring tube (20) in the third reacting station (RF3) is joined through a optical sensor (PS8) , and magnetic valves (V61) , (V74), and (V75) with the tube (til) and thereby fluidly communicated with

the dividing flask (40) . This permits the liquid in each reaction flask (10) to be extracted therefrom through the stirring tube (20) to the dividing flask (40) .

Referring still to Figs. 3A and 3B, the cooling tubes (22) in the reacting stations (RFl), (RF2) , and (RF3) are fluidly connected with a reservoir (control bath) 41 accommodating a coolant in the temperature control unit (IV) so that the coolant can be circulated through the cooling tube (22) by controlling magnetic valves (V91) and (V92) .

Further, the jacketed bath (11) is supported by a lift (12) which raises and lowers the bath (11) so that, when the lift (12) is in a raised position, the reaction chamber (10) can be dipped in the bath (11) . As shown in Fig. 4, the bath (11) has a cooling jacket (42) therearound. The jacket (42) is fluidly connected with a container (70) of the temperature control unit (IV) accommodating a coolant through a circulation pump (71) so that the coolant can be circulated through the jacket (42) by controlling the pump (71) . The bath (11) accommodates a heat transfer medium or liquid (45) therein. Also, the bath (11) has a heater (46) and a thermal sensor (96) so that the temperature of the heat transfer medium (45) can be adjusted by controlling the heater (46) depending upon an output from the thermal sensor (96) .

The bath (11) has a magnetic rotor (95) in the heat transferring medium (45) . Also, a magnetic εtirrer

(99) (see Figs. 3A and 3B) for rotating the magnetic stirrer (95) is arranged under the bath (11) so that it can rotate the magnetic stirrer (95) to stir the heat transfer medium (45) . Referring still to Figs. 3A and 3B, the reagent/solvent supply unit (III) has nine receptacles (RR1) to (RR9) for accommodating respective reagents therein and, when required, feeding one or more reagents to a designated reaction flask (10) of the reacting stations (RFl), (RF2) , or (RF3) .

Specifically, the receptacles (RR1) , (RR2) , and (RR3) are fluidly communicated through a tube (tl6) with the reaction flask (10) in the first reacting station (RFl), the receptacles (RR4) , (RR5) , and (RR6) are fluidly communicated through a tube (tl7) with the reaction flask (10) in the second reacting station (RF2) , and the receptacles (RR7) , (RR8) , and (RR9) are fluidly communicated through a tube (tl8) with the reaction flask (10) in the third reacting station (RF3) . Also, the tube (tl6) has a optical sensor (PS3) and magnetic valves (V15) , (V16) , and (V17) , the tube (tl7) has a optical sensor (PS4) and (V18) , (V19) , and (V20) , and the tube (tl8) has a optical sensor (PS5) and magnetic valves (V20) , (V21) , and (V23) . Preferably, the third reaction flask (10) may have a pH- eter (15) and the receptacles (RR7) and (RR8) may accommodate an acid reagent and an alkaline reagent,

respectively, for adjusting the pH concentration of the liquid contained in the third reaction flaεk (10) .

When feeding the reagent from one of the receptacles (RRl) to (RR9) to one of three reaction flask (10) , associated magnetic valves selected among valves (V15) to (V23) are energized and then the vacuum is introduced in the associated tube (tl6) , (tl7) , or (tl8) through the reaction chamber (10) to which the reagent will be fed, which causes the desired reagent is transported into the corresponding reaction chamber (10) . Also, the optical sensor (PS3) , (PS4) , or (PS5) detects the reagent in the tube, thereby the amount of reagent to be fed into the chamber (10) is measured.

Referring still to Figs. 3A and 3B, the reagent/solvent supply unit (III) has six commercially available receptacles (RSI) to (RS6) for accommodating respective solvents therein and, when required, feeding a certain amount of one or more reagents to a designated reaction flask (10) of the reacting stations (RFl) , (RF2) , or (RF3) . Specifically, when feeding, the selected solvent is fed out of the corresponding solvent receptacle by the vacuum introduced by a vacuum pump (60) in tubes selected among tubes (t20) to (t25) into a measuring tube (MT1) or (MT2) . Next, the solvent is measured per ten mil-liter on the basis of an output signal from a optical sensor (PSI) or (PS2) and then fed into the designated reaction chamber (10) . Preferably, a trap (61) is interposed between a de-

pressurizing pump (61) and measuring tubes (MT1) and (MT2) so that, when the optical sensor (PSI) or (PS2) has gone out of order, the pump (60) can be protected and further the solvent to be fed to the measuring tube can be decelerated.

Referring to Fig. 3B, the extract/dry unit (V) has a dividing flask (40) and two receptacles (62a) and (62b) . The dividing flask (40) divides the extracted liquid from the reaction flask (10) into two; one from an upper layer thereof and the other from an lower layer thereof, and then the divided two liquids are transported through tubes (t33) and (t34) into receptacles (62a) and

(62b) , respectively. Further, an organic substance extracted in the dividing flask (40) is introduced into a drier tube (DTI) , (DT2), or (DT3) where the substance is dehydrated and dried and then transported through tubes (t35) , (t36) , and (t37) to the reaction flask (10) of the designated reacting stations (RFl) , (RF2) , or (RF3) . The drier tubes (DTI) , (DT2) , and (DT3), suitably releasable cartridges, are fluidly communicated with the corresponding reaction chambers (10) , respectively.

Referring to Fig. 3B, the temperature control unit (IV) controls the temperature of the heat transfer medium in the jacketed baths (11) into which the reaction chambers (10) are dipped at reaction. The unit (IV) also controls the temperature of the cooling tubes (22) connected with the respective reaction flasks (10) . For

this reason, the temperature control unit (IV) includes a cooling-pipe-type cooling unit (65) and a circulation-type cooling unit (67) . The former cooling unit (65) is to circulate the heat transfer medium having a temperature of about -20°C to -10°C in the jacket (42) of each reacting station (RFl) , (RF2) , or (RF3) . On the other hand, the latter cooling unit (67) is to circulate a cooling water in a waste-liquid tank (66) at concentration thereby recovering the solvent and to circulate the cooling water in the cooling tubes (22) at heat reaction.

The cooling-pipe-type cooling unit (65) , having a heater (68) , a cooling-pipe-type cooler (69) , and an insulated heat bath (70) , cools the heat transfer medium down to a certain temperature from about -20°C to -10°C and then circulates it in the desired jacketed bath (11) using a circulating pump (71) and magnetic valves (V89) and (V90) . The bath (11) has a heater (46) and a thermal sensor (96) so that a reaction temperature is adjusted to a predetermined temperature. The circulation-type cooling unit (67) , on the other hand, has a circulation-type cooler (72) . The cooler (72) is fluidly communicated with a waste-liquid tank (66) and an insulated bath (41) so that the cooling water can always be circulated in the tank (66) for cooling it. If necessary, the cooling water is also circulated in the cooling tube (22) connected with the reaction flask (10) using a circulating pump (73) and magnetic valves

(V91 ) and ( V92 ) .

The above described units in the automated synthesizing device are electrically communicated with the computer (5) through interfaces (not shown) and thereby automatically operated by controlling the magnetic valves and relays (not shown) in accordance with an operation programs stored in the computer (5) . The operation programs includes a first program for controlling the operations of magnetic valves and relays, a second program for performing the reactions, and a third program for arranging procedures of the synthesizing processes.

Prior to an operation of the device of the invention for simultaneously synthesizing a variety of compounds, a synthesizing program is prepared by which a plurality of chemical materials required for the reaction to be performed are selected and then fed to the reaction flask (10) of the first reacting station (RFl) . According to the program, for example, a basic material (A) and the mixing three materials (B) , (C) , and (D) are selected. The materials (B) , (C) , and (D) , which do not react each other, reacts only with the material (A) to synthesize the desired compounds (A+B) , (A+C) , and (A+D) . Then, another three materials (E) , (F) , and (G) , which do not react each other, are selected for reacting them with the firstly synthesized compounds (A+B) , (A+C) , and (A+D) to synthesize nine compounds (A+B+E) , (A+B+F) , (A+B+G) , (A+C+E) , (A+C+F) , (A+C+G) , (A+D+E) , (A+D+F) , and (A+D+G) . Further, another

three materials (H) , (I) , and (J) , which do not react each other, are selected for react them with the secondly synthesized nine compounds to synthesize twenty-seven compounds but not react each other. Furthermore, another materials are selected that can react with the secondly synthesized twenty-seven compounds. Thus, an enormous number of compounds will be synthesized cumulatively.

Alternatively, the program may be so changed that the three materials are reacted with three other materials to synthesize nine compounds at first reaction, and then the nine compounds are reacted with three other materials to synthesize twenty-seven compounds.

In the automated synthesizing device so programmed, the selected materials are supplied from the material supply unit (I) to the reaction flask (10) of the first reacting station (RFl) where the materials are reacted to synthesize a plurality of compounds.

Specifically, the basic material (A) is supplied from the receptacle (CR1) of the material supply unit (I) to the reaction flask (10) through the branch tube (tlOO) and common tube (tlOl) . Then the material (B) in the receptacle (CR2) , the material (C) in the receptacle (CR3) , and the material (C) in the receptacle (CR3) are sequentially supplied to the same reaction flask (10) . As described, the basic material (A) can react with other materials (B) , (C) , and (D) but the materials (B) , (C) , and (D) do not react each other.

In the reaction flask (10) of the first reacting station (RFl) , the materials (A) , (B) , (C) , and (D) are reacted, thereby simultaneously synthesizing three compounds (A+B) , (A+C) , and (A+D) . For this reaction, the desired one or more reagents and solvents are fed to the same reaction flask (10) from the corresponding reagent accommodating receptacles (RFl) to (RF9) and solvent accommodating receptacles (RSI) to (RS6) . Also, the computer controls the sequence of processes, such as the heating, cooling, and stirring, according to the predetermined conditions.

The liquid containing the three compounds synthesized in the reaction chamber (10) of the first reacting station (RFl) is then transported through the stirring tube (20) to the dividing flask (40) where it is divided or to another reaction flask (10) of the reacting station (RF2) or (RF3) for providing the same with the after-treatment, and subsequently returned to the reaction flask (10) of the first reacting station (RFl) . Then, in the second reaction, other materials are fed from the material supply unit (I) to the reacting flask (10) of the first reacting station (RFl) . Specifically, the materials (E) , (F) , and (G) are fed from the respective receptacles (CR5) , (CR6) , and (CR7) into the reaction flask (10) of the first reacting station (RFl) . By so adding the three materials (E) , (F) , and (G) to the three compounds synthesized in the firεt reaction, nine compoundε are newly

synthesized.

Fig. 5 shows a second embodiment of the material supply unit (I) . This material supply unit (I) can be equally incorporated in the automated synthesizing device described above. In this embodiment, the receptacles (1') (CR1 to CR9) are designed to accommodate a large amount of respective materials. Also, the receptacles (1') are fluidly communicated through respective branch tubes (tlOO) and magnetic valves (V100) to (V108) with a common tube (tlOl) which is in turn communicated with a measuring pump

(150) on its downstream side, thereby the materials are measured by the pump (150) to a certain amount and then fed to the reaction flask (10) of the first reacting station

(RFl) . The measuring pump (150) has the same structure as the pump disclosed in the Japanese Patent Laid-Open Publication No. 7-265833 filed by the applicant. As shown in Fig. 6, the pump (150) has a vertical syringe (151) and a piston (153) movably arranged in the syringe in sealingly contact with an inner periphery surface thereof. The piston (153) is joined to a piston rod (152) which is inserted through a bottom of the syringe. Therefore, pulling the piston (153) downward permits the pump (150) to suck a certain amount of liquid (material) , which corresponds to a moved distance of the piston (153) , into the syringe (151) and then pushing the piston (153) upward permits the pump (150) to discharge the liquid into the

flask (10) of the first reacting station (RFl) . Namely, the amount of the material to be fed to the reaction flask (10) can be adjusted by the downward movement of the piston (153) . For this purpose a motor (154) is drivingly coupled to a vertical lead screw (155) . The piston rod

(152) is fixed to a movable stage (156) having a threaded hole (156a) in which the lead screw (155) is inserted. Therefore, driving the motor (154) to rotate the lead screw (155) permits the εtage (156), piston rod (152) , and piston

(153) to move up and down.

An uppermost end of the syringe (151) is closed by a syringe head (160) . The head (160) includes therein an inlet (160a) and an outlet (160b) which extend from its bottom surface to its top surface. Also, the head (160) has in its bottom surface a shortcut passage (160c) , or groove, so that, when the piston is in the uppermost position in close contact with the bottom surface of the head (160) , the shortcut passage (160c) is formed to communicate between the inlet (160a) and the outlet (160b) .

The branch tube (tlOO) has an optical sensor (PS) and the common tube (tlOl) includes on upεtream and downstream sides of the pump (150) respective optical sensors (PS) for detecting the material transported therethrough. Also, an upεtream end of the common tube (tlOl) is fluidly communicated through a magnetic valve (V114) with a receptacle (WS) accommodating a rinsing

liquid and a presεure pump (PP) through a magnetic valve (V112) .

The materials in the material supply unit (I) are supplied to the reaction flask (10) of the first reacting station (RFl) as described in the first embodiment. Namely, materials from the receptacles (l') are sequentially measured by the measuring pump (150) and then supplied to the reaction flask (10) where they are simultaneously reacted to synthesize a plurality of compounds.

Fig. 7 shows a third embodiment of the material supply unit (I) . Similar to the second embodiment, the unit (I) includes the measuring pump (150) in the common tube (tlOl) so that each material from the material accommodating receptacle (1') is measured and then fed to the reaction flask (10) of the first reacting station (RFl) .

Particularly, the unit has a six-way rotary valve (170) which includes six ports (170a) to (170f) . Among them, five ports (170a) to (170e) are fluidly communicated through branch tubes (tlOO) with material accommodating receptacles (1') , or (CR1) to (CR5) , respectively. T h e remaining port (170f) is connected through a tube (tl20) with magnetic valves (130) and then (131) which is in turn connected with a rinsing liquid accommodating receptacle (WS) through a tube (tl21) and a presεure pump (PP) through a tube (tl22) .

With this material supply unit (I) , when feeding the material to the reaction flask (10) of the first reacting station (RFl) , the computer (5) drives the rotary valve (170) to cause the desired material to be transported through the measuring pump (150) to the reaction flask (10) .

According to this embodiment, materials can be transported from their receptacles (1') to the reaction flask (10) in a same time period. That iε, thiε arrangement can eliminate time differenceε, for transporting materials from their receptacles to the reaction flask, which would occurred when employing the material supply unit shown in Fig. 2. Therefore, the materials to be transported to the reaction flask can be accurately measured.

Further, although the material supply unit shown in Fig. 2 requires the same number of serially connected magnetic valves as the receptacles, one or only a few rotary valves are required for controlling the feeding of materials in this embodiment and thereby the control program of the computer (5) can be simplified.

Figs. 8A and 8B show a fourth embodiment of the invention in which the receptacles (RRl) to (RR9) are used as a material supply unit (I') . The receptacles (RRl) to (RR9) are fluidly communicated through corresponding branch tubes (tlOO) to respective magnetic valves disposed serially in the common tube (tlOl) . The common tube (tlOl)

is further fluidly communicated through a magnetic valve (Vlll) to one end of the tube (t4) , the other end thereof being communicated with the flask (10) of the first reacting station (RFl) . Further, although the six receptacles are used for accommodating respective solvents in the first embodiment, it may be so changed that three of them (RSI) to (RS3) are used for accommodating respective solventε while the remaining three of them (RS4) to (RS6) are used for accommodating respective reagents. In this instance, the receptacles (RSI) to (RS6) are fluidly communicated with each of reaction flasks (10) of the first to third reacting stations (RFl) to (RF3) .

Like other embodiments, in this embodiment, a plurality of selected materials are fed from the material accommodating receptacles (RRl) to (RR9) of the material supply unit (I') to the reaction flask (10) of the first reacting station (RFl) where a plurality of reactions are simultaneouεly performed to synthesize a number of chemical compounds.

Figs. 9A and 9B show a fifth embodiment of the invention. Note that each solid line terminated at right hand side of Fig. 9A should be connected with corresponding solid line terminated at left hand side of Fig. 9B. The illustrated automated synthesizing device, which is a combination of an automated synthesizing device discloεed in the Japanese Patent Laid-Open Publication No.

5-192563 filed by the applicant and the material supply unit described in the first to third embodiments. This synthesizing device further includes the analyzing unit (VI) , or reaction tracing unit, for analyzing the synthesized chemical compounds, the refining unit (VII) , having a fraction collector, for refining the synthesized chemical compounds, a rinsing unit (VIII) , a pH control unit (IX) , a dividing unit (X) . Alεo arranged in thiε εynthesizing device are measuring tubes (MT) for measuring the reagents and solvents fed from the reagent and solvent accommodating receptacleε to the reaction flasks in the reaction unit (II) - In addition, a flow line (k) is connected at one end with the reaction flask (10) of the first reacting station (RFl) and an opposite end with the material supply unit (I) .

The reaction tracing unit (VI) , which includes a column (200) for a high performance liquid chromatography to analyze the chemical compound, samples a part of the chemical compounds synthesized in the reaction unit (II) and then introduces it into the column (200) for analyzing it to determine a proceeding of the reaction. Note that containers accommodating developing solvents are indicated by reference numerals (201) and (202) , respectively.

The refining unit (VII) takes all the automatically synthesized chemical compoundε into a column for a high performance liquid chromatography while preventing air from being mixed in to provide them with a

peak division known in the art. The divided liquids are collected in the fraction collector (300) . Specifically, all the content, i.e., synthesized compounds, in the reaction flask (10) is removed therefrom to a reservoir (SR10) where it is housed for a short while. The compoundε are putted into a εample loop and then tranεported by the use of a high performance liquid chromatography pump HP2 to column (204) and/or (205) where they are refined by a column chromatography process according to a predetermined refining conditions. In Fig. 9B, (206) and (207) are containers for accommodating respective developing solvents and (208) is a detector in which an ultraviolet-ray absorption of an introduced liquid is measured.

The refined liquids from the column (204) and (205) are then introduced into the detector (208) where the ultraviolet-ray absorption thereof is measured. Subsequently, the liquid iε fed into the fraction collector (300) where it iε divided for a plurality of containers (301) . Each refined liquid in the container (301) may be supplied to any of the reaction flasks (10) in the reacting stations (RFl) to (RF3) .

Thus, according to this embodiment, the synthesized chemical compounds can be transported from any of the reacting stations (RFl), (RF2) , or (RF3) to the high performance liquid chromatography for refining. Also, the liquid, which is refined in the high performance liquid chromatography and then collected in the fraction collector

(300) , can be transported to the reaction flask (10) of the first reacting station (RFl) where it is uεed aε a material to be reacted with other aterialε εupplied therein to simultaneously synthesize a plurality of compounds. Further, by the repetition of this procedure, an great number of chemical compoundε can be produced.

Further, using a sample exchanger shown in Figs. 10 and 11, discloεed in Japanese Patent Laid-Open Publication No. 7-39770 filed by the applicant for the fraction collector (300) allows the refined liquid to be divided for more containers (301) , thereby synthesizing a greater number of new compounds in the reaction flask (10) in the reacting stations (RFl) to (RF3) .

The sample exchanger (310) has a rotatably supported εtage (311) and a number of, e.g., thirty, containerε (301) mounted on the stage (311) . These containers (301) are arranged in double circles. The exchanger (310) also has a nozzle (312) above the containers which can be moved up and down and extended radially. The nozzle (312) is fluidly communicated through a three-way valve (not shown) with the refining unit (VII) shown in Fig. 9B for supplying the liquid from the column to each containers (301) and with the reaction flasks (10) of the reacting stations (RFl) to (RF3) . With this sample exchanger (310) , thirty compounds can be synthesized simultaneously and then independently accommodated in corresponding containers

(301) . Also, a great number of compounds can be efficiently synthesized by using the compounds in the containers (301) as materials, within a reduced period of time. In conclusion, although the prior art automated synthesizing device syntheεizeε only one compound through one reaction, the automated synthesizing device of the invention can provide a plurality of compounds through a single reaction. For example, by supplying and reacting N materials with M materials, N>M compounds are simultaneously synthesized through a single reaction. Further, by supplying P materials with the N ^« M compounds, N'M'P compounds can be synthesized. Therefore, by repeating such reactions, the number of the synthesized compounds will increase exponentially, which reduces time for synthesizing a number of compounds.

Also, with the synthesizing device having the rotary valve in the material supply unit, the material accommodating receptacles can be arranged around the valve, which simplifies the structure of the unit and the control program for controlling the unit.

Further, with the synthesizing device having the analyzing unit, a mixing ratio of the variety of compounds synthesized in a firεt reaction can be detected and the second reaction can be performed with reference to the result of the detection. Therefore, more effective synthesizing of the compounds can be accomplished.

Furthermore, with the synthesizing device having the refining unit, the compound can be refined by removing impurities therefrom to produce highly purified compounds.

Besides, the purified compounds can be used as materials for synthesizing further compounds.

As described above, the automated synthesizing device of the invention is the improvement of the prior art synthesizing device to which the material supply unit is added, thereby a great number of compounds can be efficiently synthesized in accordance with the control program in a reduced period of time.