WO1997024181A1 - Appareil et procede de synthese de divers composes chimiques en un seul lot - Google Patents

Appareil et procede de synthese de divers composes chimiques en un seul lot Download PDF

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Publication number
WO1997024181A1
WO1997024181A1 PCT/JP1996/003728 JP9603728W WO9724181A1 WO 1997024181 A1 WO1997024181 A1 WO 1997024181A1 JP 9603728 W JP9603728 W JP 9603728W WO 9724181 A1 WO9724181 A1 WO 9724181A1
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WO
WIPO (PCT)
Prior art keywords
reaction chamber
reaction
compounds
receptacles
materials
Prior art date
Application number
PCT/JP1996/003728
Other languages
English (en)
Inventor
Tohru Sugawara
Shinji Kato
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to EP96942594A priority Critical patent/EP0876207A1/fr
Priority to AU11719/97A priority patent/AU1171997A/en
Priority to CA 2239037 priority patent/CA2239037A1/fr
Publication of WO1997024181A1 publication Critical patent/WO1997024181A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • B01J19/004—Multifunctional apparatus for automatic manufacturing of various chemical products

Definitions

  • 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.
  • 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.
  • 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.
  • the resulting chemical compound is analyzed and then refined.
  • 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.
  • 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.
  • 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.
  • 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.
  • the material may be a single material or a mixture of a plurality of liquid materials.
  • 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.
  • 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.
  • 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.
  • a measuring device disclosed in Japanese Patent Laid-Open Publication No. 7-265833 is preferably employed.
  • 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.
  • 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 fir ⁇ t or second reaction chamber.
  • conditions for example, temperature
  • the reaction conditions can be controlled precisely.
  • 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.
  • the synthesizing device may include a refining unit for removing impurities from the compound synthesized in the first or second reaction chamber.
  • 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.
  • 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 fir ⁇ t 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.
  • Fig. 11 is a plan view of the sample exchanger.
  • 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.
  • 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) .
  • 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.
  • the synthe ⁇ ized 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.
  • 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.
  • a reference material (A) and three other materials (B) , (C) , and (D) are fed from the material supply unit (I) into the first reaction camber (10) .
  • the material (A) is reacted with other materials (B) , (C) , and (D) .
  • three different chemical compounds (A+B) , (A+C) , and (A+D) are synthesized.
  • the automated synthesizing device illustrated in Figs. 2, 3A and 3B, of the invention includes a plurality of flow lines illu ⁇ trated 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.
  • 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.
  • 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.
  • 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.
  • the material supply unit (I) has ten receptacles (1), or (CR1) to (CR10) , for accommodating respective liquid materials.
  • 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.
  • 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) 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.
  • 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
  • the above described material supply unit (I) supplies the required materials from receptacles (1) selected by the computer (5) .
  • the basic material (A) is fed from the receptacle (CR1) to the reaction flask (10) of the first reacting station (RF1) .
  • mixing materials (B) , (C) , and (D) accommodated in respective receptacles (CR2) , (CR3), and (CR4) are fed to the same reaction flask (10) of the fir ⁇ t reacting station (RFl) .
  • these mixing materials are selected so that they can not react each other.
  • 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) .
  • 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) .
  • 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.
  • 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 fir ⁇ t 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) .
  • 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) .
  • 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) .
  • 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) .
  • 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) .
  • 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) .
  • 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) .
  • 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) .
  • 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.
  • 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) .
  • a magnetic ⁇ tirrer (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) .
  • 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) .
  • 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)
  • the receptacles (RR7) , (RR8) , and (RR9) are fluidly communicated through a tube (tl8) with the reaction flask (10) in the third reacting station (RF3) .
  • 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)
  • the tube (tl8) has a optical sensor (PS5) and magnetic valves (V20) , (V21) , and (V23)
  • 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 fla ⁇ k (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) .
  • 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.
  • 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) .
  • 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) .
  • 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) .
  • 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.
  • 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
  • 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.
  • 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) .
  • 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) .
  • 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) 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.
  • 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) .
  • 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) .
  • 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.
  • 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.
  • 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.
  • the materials (A) , (B) , (C) , and (D) are reacted, thereby simultaneously synthesizing three compounds (A+B) , (A+C) , and (A+D) .
  • 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) .
  • 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) .
  • other materials are fed from the material supply unit (I) to the reacting flask (10) of the first reacting station (RFl) .
  • 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) .
  • the three materials (E) , (F) , and (G) are added to the three compounds synthesized in the fir ⁇ t reaction, nine compound ⁇ 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.
  • the receptacles (1') (CR1 to CR9) are designed to accommodate a large amount of respective materials.
  • 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
  • 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.
  • 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 up ⁇ tream and downstream sides of the pump (150) respective optical sensors (PS) for detecting the material transported therethrough. Also, an up ⁇ tream end of the common tube (tlOl) is fluidly communicated through a magnetic valve (V114) with a receptacle (WS) accommodating a rinsing liquid and a pres ⁇ ure pump (PP) through a magnetic valve (V112) .
  • V114 magnetic valve
  • WS receptacle
  • PP pres ⁇ ure pump
  • 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) .
  • the unit has a six-way rotary valve (170) which includes six ports (170a) to (170f) .
  • 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 pres ⁇ ure pump (PP) through a tube (tl22) .
  • WS rinsing liquid accommodating receptacle
  • PP pres ⁇ ure pump
  • 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) .
  • materials can be transported from their receptacles (1') to the reaction flask (10) in a same time period. That i ⁇ , thi ⁇ arrangement can eliminate time difference ⁇ , 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.
  • 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) .
  • 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 solvent ⁇ while the remaining three of them (RS4) to (RS6) are used for accommodating respective reagents.
  • the receptacles (RSI) to (RS6) are fluidly communicated with each of reaction flasks (10) of the first to third reacting stations (RFl) to (RF3) .
  • 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 simultaneou ⁇ ly 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 disclo ⁇ ed 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) .
  • Al ⁇ o arranged in thi ⁇ ⁇ ynthesizing device are measuring tubes (MT) for measuring the reagents and solvents fed from the reagent and solvent accommodating receptacle ⁇ to the reaction flasks in the reaction unit (II) -
  • 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.
  • containers accommodating developing solvents are indicated by reference numerals (201) and (202) , respectively.
  • the refining unit (VII) takes all the automatically synthesized chemical compound ⁇ 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) .
  • 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 compound ⁇ are putted into a ⁇ ample loop and then tran ⁇ ported 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.
  • (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 i ⁇ fed into the fraction collector (300) where it i ⁇ 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) .
  • 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.
  • 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 u ⁇ ed a ⁇ a material to be reacted with other aterial ⁇ ⁇ upplied therein to simultaneously synthesize a plurality of compounds. Further, by the repetition of this procedure, an great number of chemical compound ⁇ can be produced.
  • the sample exchanger (310) has a rotatably supported ⁇ tage (311) and a number of, e.g., thirty, container ⁇ (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) .
  • 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.
  • 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.
  • the synthesizing device having the analyzing unit a mixing ratio of the variety of compounds synthesized in a fir ⁇ t 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.
  • the purified compounds can be used as materials for synthesizing further compounds.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un dispositif de synthèse automatisé permettant d'effectuer simultanément la synthèse de divers composés chimiques. Ce dispositif comprend plusieurs réceptacles (CR) destinés à recevoir des matières liquides respectives, ainsi qu'un ballon de réaction (10) se trouvant en communication fluidique avec lesdits réceptacles. Lors du processus de synthèse, plusieurs matières choisies sont introduites dans le ballon de réaction (10) où sont effectuées plusieurs réactions chimiques de manière à synthétiser simultanément plusieurs composés. D'autres matières sont ensuite introduites dans le ballon de réaction, à l'intérieur duquel il est ainsi possible de synthétiser simultanément un grand nombre de nouveaux composés.
PCT/JP1996/003728 1995-12-29 1996-12-20 Appareil et procede de synthese de divers composes chimiques en un seul lot WO1997024181A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96942594A EP0876207A1 (fr) 1995-12-29 1996-12-20 Appareil et procede de synthese de divers composes chimiques en un seul lot
AU11719/97A AU1171997A (en) 1995-12-29 1996-12-20 Apparatus and method for synthesizing a variety of chemical compounds in a single batch
CA 2239037 CA2239037A1 (fr) 1995-12-29 1996-12-20 Appareil et procede de synthese de divers composes chimiques en un seul lot

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP35373995 1995-12-29
JP7/353739 1995-12-29

Publications (1)

Publication Number Publication Date
WO1997024181A1 true WO1997024181A1 (fr) 1997-07-10

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PCT/JP1996/003728 WO1997024181A1 (fr) 1995-12-29 1996-12-20 Appareil et procede de synthese de divers composes chimiques en un seul lot

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EP (1) EP0876207A1 (fr)
AU (1) AU1171997A (fr)
WO (1) WO1997024181A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2146030A (en) * 1983-09-02 1985-04-11 Nippon Zeon Co Polynucleotide synthesizing apparatus
EP0332452A1 (fr) * 1988-03-11 1989-09-13 Takeda Chemical Industries, Ltd. Appareil de synthèse automatique
EP0510487A1 (fr) * 1991-04-17 1992-10-28 Takeda Chemical Industries, Ltd. Appareil de synthèse automatique et procédé pour commander le fonctionnement de l'appareil
JPH0679166A (ja) * 1992-03-19 1994-03-22 Takeda Chem Ind Ltd 合成反応装置

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2146030A (en) * 1983-09-02 1985-04-11 Nippon Zeon Co Polynucleotide synthesizing apparatus
EP0332452A1 (fr) * 1988-03-11 1989-09-13 Takeda Chemical Industries, Ltd. Appareil de synthèse automatique
EP0510487A1 (fr) * 1991-04-17 1992-10-28 Takeda Chemical Industries, Ltd. Appareil de synthèse automatique et procédé pour commander le fonctionnement de l'appareil
JPH0679166A (ja) * 1992-03-19 1994-03-22 Takeda Chem Ind Ltd 合成反応装置

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 018, no. 334 (C - 1216) 24 June 1994 (1994-06-24) *

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AU1171997A (en) 1997-07-28
EP0876207A1 (fr) 1998-11-11

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