Automated synthesis apparatus and method of controlling the apparatus

• US 5,499,193 A
• Filed: 06/21/1993
• Issued: 03/12/1996
• Est. Priority Date: 04/17/1991
• Status: Expired due to Fees

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Kato, Shinji, Sugawara, Tohru
• Primary Examiner(s): Voeltz, Emanuel T.
• Assistant Examiner(s): Assouad, Patrick J.
• Application Number:
  US08/079,375
• Time in Patent Office: 995 Days
• Field of Search: 364/500, 364/496, 364/502, 364/497, 422/70, 422/68.1, 422/62, 422/63, 422/67, 422/81, 422/135, 422/138, 436/161, 436/180
• US Class Current: 700/268
• CPC Class Codes: B01J 19/004 Multifunctional apparatus for automatic manufacturing of various chemical products sequential reactions B01J19/0046

Abstract

An automatic synthesizing apparatus for continuously effecting automatically by a controlling apparatus all the operations including the supplying of samples into reaction vessel and so on, reaction processing of the contents within the reaction vessels, PH adjustment, extraction/dehydration processing, purification of the contents, and further analysis of the reaction condition so as to produce the target compounds. Many basic unit operation procedures are made and stored so that programs for effecting the operation controlling of the automatic synthesizing apparatus may be extremely easily made. The innumerable syntheses programs in the chemical experiments may be effected simply by the inputting of the operation names of the unit operation procedures in the operational orders when the synthesis order programs may be made for each target compound.

Claims

1. An automated synthesis apparatus comprising;

a synthesis processing apparatus including;

a means for shifting contents of at least one container selected from a plurality of storing containers including reaction vessels to another container;

a reaction means for reacting the contents of selected reaction vessels;

an analyzing means for analyzing with analyzers at least one portion of the contents taken out from the reaction vessels;

a purifier means for separating and purifying with purifiers at least one material from the contents of the reaction vessels; and

a restoring means for restoring each of said means of said synthesis processing apparatus to their initial conditions; and

a control apparatus including;

a storing means for storing in advance a plurality of unit operating procedures, each of said unit operating procedures operating one of said means of said synthesis processing apparatus;

a compiler means for compiling at least one unit operating procedure selected by said storing means for setting up an operating procedure for synthesizing a specific target compound;

an organizing means for selecting from and connecting together each means of said synthesis processing apparatus in accordance with the operating procedure of the compiler means to set up control procedures for operating all of the selected means of the synthesis processing apparatus in sequence; and

an operating means of a computer for actuating the control procedures to operate each means of said synthesis processing apparatus for synthesizing the specific target compound.

2. The automated synthesis apparatus in accordance with claim 1, wherein the shifting means is provided for moving the contents to another container from one container in said synthesis processing apparatus and for circulating the contents of the container within flow lines which communicate mutually with the respective means and among components of the respective means, including opening and closing valve means and quantifiers;

and wherein sensors are interposed among the flow lines, and wherein the opening and closing valve means, the quantifiers, and the sensors are connected to said control apparatus.

3. The automated synthesis apparatus in claim 1 or 2, wherein the shifting means includes a device for moving the contents by applying a pressure thereto or a device for moving the contents by gravity.

4. The automated synthesis apparatus in accordance with claim 1 or 2, wherein the reacting means comprises at least one of:

a temperature means for controlling the reaction temperature of the contents;

a stirring means for stirring the contents;

a dropping means for dropping the contents to effect an addition;

a timer means for controlling the reaction time of the contents;

a drying means for drying the contents;

a means of extracting the specific reaction mixture from the contents.

5. The automated synthesis apparatus in accordance with claim 1 or 2, wherein the respective means of the synthesis processing apparatus comprise:

a sample supply unit provided with;

a plurality of storing containers for storing raw materials, reagents,

solvents, pH adjusting liquids;

a means for automatically feeding the sample from storing cells to the storing containers, a volumetric tube and a sensor for measuring the samples to be transported from the storing containers;

a flow line for a flowing operation from each of the storing container to another element of said synthesis processing apparatus, and an electromagnetic valve for opening and closing flow passages interposed in each flow line;

a reaction unit composed of;

a reaction vessel unit;

an extraction/dehydration unit;

a pH adjusting unit and a reaction unit, provided with a plurality of reaction vessels and pH adjusting vessels;

flow lines for feeding a sample of an optional storing container from among storing containers provided in the sample supply unit;

flow lines provided for circulating samples among the plurality of reaction vessels, and among these reaction vessels and pH compensating vessels;

extraction/separation funnels and dehydrating tubes provided for circulating samples through the flow lines among the respective vessels, a means for analyzing a reaction liquid connected through the respective reaction vessels and flow lines; and

electromagnetic valves for opening and closing the flow passages interposed in the respective flow lines;

a purifying unit provided with a purifier connected to the respective reaction vessels and flow lines provided in the reaction units, and to a fraction collector so as to feed an optional purified product collected in the fraction collector through the flow lines to the reaction vessels of the reaction units;

a temperature control unit provided with a means for circulating hot media or cold media to heat or cool the reaction vessels and a separate heater for also heating the reaction vessels;

a washing unit for transporting the washing liquid to the reaction vessels and quantifying devices.

6. The automated synthesis apparatus in accordance with claim 1 or 2, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

17. The automated synthesis apparatus in accordance with claim 3, wherein the reacting means comprises at least one of:

a temperature means for controlling the reaction temperature of the contents;

a stirring means for stirring the contents;

a dropping means for dropping the contents to effect an addition;

a timer means for controlling the reaction time of the contents;

a drying means for drying the contents;

a means of extracting the specific reaction mixture from the contents.

18. The automated synthesis apparatus in accordance with claim 3, wherein the respective means of the synthesis processing apparatus comprise:

a sample supply unit provided with;

plurality of storing containers for storing raw materials, reagents, solvents, pH adjusting liquids;

a means for automatically feeding the sample from storing cells to the storing containers, a volumetric tube and a sensor for measuring the samples to be transported from the storing containers;

a flow line for a flowing operation from each of the storing container to another element of said synthesis processing apparatus, and an electromagnetic valve for opening and closing flow passages interposed in each flow line;

a reaction unit composed of;

a reaction vessel unit;

an extraction/dehydration unit;

a pH adjusting unit and a reaction unit, provided with a plurality of reaction vessels and pH adjusting vessels;

flow lines for feeding a sample of an optional storing container from among storing containers provided in the sample supply unit;

flow lines provided for circulating samples among the plurality of reaction vessels, and among these reaction vessels and Ph compensating vessels;

extraction/separation funnels and dehydrating tubes provided for circulating samples through the flow lines among the respective vessels, a means for analyzing a reaction liquid connected through the respective reaction vessels and flow lines; and

electromagnetic valves for opening and closing the flow passages interposed in the respective flow lines;

a purifying unit provided with a purifier connected to the respective reaction vessels and flow lines provided in the reaction units, and to a fraction collector so as to feed an optional purified product collected in the fraction collector through the flow lines to the reaction vessels of the reaction units;

a temperature control unit provided with a means for circulating hot media or cold media to heat or cool the reaction vessels and a separate heater for also heating the reaction vessels;

a washing unit for transporting the washing liquid to the reaction vessels and quantifying devices.

19. The automated synthesis apparatus in accordance with claim 4, wherein the respective means of the synthesis processing apparatus comprise:

a sample supply unit provided with;

a plurality of storing containers for storing raw materials, reagents,

solvents, pH adjusting liquids;

a means for automatically feeding the sample from storing cells to the storing containers, a volumetric tube and a sensor for measuring the samples to be transported from the storing containers;

a flow line for a flowing operation from each of the storing container to another element of said synthesis processing apparatus, and an electromagnetic valve for opening and closing flow passages interposed in each flow line;

a reaction unit composed of;

a reaction vessel unit;

an extraction/dehydration unit;

a pH adjusting unit and a reaction unit, provided with a plurality of reaction vessels pH adjusting vessels;

flow lines for feeding a sample of an optional storing container from among storing containers provided in the sample supply unit;

flow lines provided for circulating samples among the plurality of reaction vessels, and among these reaction vessels and pH compensating vessels;

extraction/separation funnels and dehydrating tubes provided for circulating samples through the flow lines among the respective vessels, a means for analyzing a reaction liquid connected through the respective reaction vessels and flow lines; and

electromagnetic valves for opening and closing the flow passages interposed in the respective flow lines;

a purifying unit provided with a purifier connected to the respective reaction vessels and flow lines provided in the reaction units, and to a fraction collector so as to feed an optional purified product collected in the fraction collector through the flow lines to the reaction vessels of the reaction units;

a temperature control unit provided with a means for circulating hot media or cold media to heat or cool the reaction vessels and a separate heater for also heating the reaction vessels;

a washing unit for transporting the washing liquid to the reaction vessels and quantifying devices.

20. The automated synthesis apparatus in accordance with claim 17, wherein the respective means of the synthesis processing apparatus comprises:

a sample supply unit provided with;

a plurality of storing containers for storing raw materials, reagents, solvents, pH adjusting liquids;

a means for automatically feeding the sample from storing cells to the storing containers, a volumetric tube and a sensor for measuring the samples to be transported from the storing containers;

a flow line for a flowing operation from each of the storing container to another element of said synthesis processing apparatus, and an electromagnetic valve for opening and closing flow passages interposed in each flow line;

a reaction unit composed of;

a reaction vessel unit;

an extraction/dehydration unit;

a pH adjusting unit and a reaction unit, provided with a plurality of reaction vessels pH adjusting vessels;

flow lines for feeding a sample of an optional storing container from among storing containers provided in the sample supply unit;

flow lines provided for circulating samples among the plurality of reaction vessels, and among these reaction vessels and pH compensating vessels;

extraction/separation funnels and dehydrating tubes provided for circulating samples through the flow lines among the respective vessels, a means for analyzing a reaction liquid connected through the respective reaction vessels and flow lines; and

electromagnetic valves for opening and closing the flow passages interposed in the respective flow lines;

a purifying unit provided with a purifier connected to the respective reaction vessels and flow lines provided in the reaction units, and to a fraction collector so as to feed an optional purified product collected in the fraction collector through the flow lines to the reaction vessels of the reaction units;

a temperature control unit provided with a means for circulating hot media or cold media to heat or cool the reaction vessels and a separate heater for also heating the reaction vessels;

a washing unit for transporting the washing liquid to the reaction vessels and quantifying devices.

21. The automated synthesis apparatus in accordance with claim 3, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

22. The automated synthesis apparatus in accordance with claim 4, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

23. The automated synthesis apparatus in accordance with claim 5, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

24. The automated synthesis apparatus in accordance with claim 17, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

25. The automated synthesis apparatus in accordance with claim 18, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

26. The automated synthesis apparatus in accordance with claim 19, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

27. The automated synthesis apparatus in accordance with claim 20, wherein the control apparatus controls the driving of the synthesis processing apparatus in accordance with an inputted synthesis procedure program, and also, enables a manual input of an interrupt program during the execution of the synthesis procedure program so that the control of the synthesis processing apparatus may be effected in accordance with the manually inputted interrupt program.

28. The automated synthesis apparatus in accordance with claims 1 or 2, wherein the respective means of the synthesis processing apparatus comprise:

a sample supply unit provided with;

a plurality of storing containers for storing raw materials, reagents, solvents, pH adjusting liquids;

a means for automatically feeding the sample from storing cells to the storing containers, a volumetric tube and a sensor for measuring the samples to be transported from the storing containers;

a flow line for flowing operation from each of the storing container to another element of said synthesis processing apparatus and an electromagnetic valve for opening and closing flow passages interposed in each flow line;

a reaction unit composed of;

a reaction vessel unit;

an extraction/dehydration unit;

a pH adjusting unit and a reaction unit, provided with a plurality of reaction vessels and pH adjusting vessels;

flow lines for feeding a sample of an optional storing container from among storing containers provided in the sample supply unit;

flow lines provided for circulating samples among the plurality of reaction vessels, and among these reaction vessels and pH compensating vessels;

extraction/separation funnels and dehydrating tubes provided for circulating samples through the flow lines among the respective vessels, a means for analyzing a reaction liquid connected through the respective reaction vessels and flow lines; and

electromagnetic valves for opening and closing the flow passages interposed in the respective flow lines;

a purifying unit for separating each of upper and lower layers of a separated liquid by utilizing the difference in electrical conductivity of the upper and lower layers and connected through the respective reaction vessels and flow lines provided in the reaction units, and with a fraction collector so as to feed an optional purified products collected to the fraction collector through the flow lines to the reaction vessels of the reaction units;

a temperature control unit provided with a means for circulating hot media or cold media to heat or cool the reaction vessels and a separate heater for also heating the reaction vessels;

a washing unit for transporting the washing liquid to the reaction vessels and quantifying devices.

29. An apparatus in accordance with claim 28, wherein the purifying unit comprises:

an electode provided for measuring in a plurality of level positions the electric conduction degree of a solution within a cell, and a deciding means for deciding whether or not the electric conduction degree detected in the plurality of level positions becomes the same as the measured value at the previous time.

30. An apparatus in accordance with claim 28, wherein the purifying unit comprises:

a pair of electrodes for measuring the electrode conduction degree of a solution to be discharged from a cell, and a deciding means for deciding whether or not variations are caused in the electric conduction degree measured by the opposite electrode.

31. An apparatus in accordance with claim 28, wherein the purifying unit comprises:

an electrode provided for measuring in a plurality of level positions the electric conduction degree of a solution within a cell, a pair of opposite electrodes for measuring the electric conduction degree of the solution to be discharged from the cell, a first deciding means for deciding whether or not the electric conduction degree detached in the plurality of level positions has become the same as the measured value at the previous time, and a second deciding means for deciding whether or not the vibrations are caused in the electric conduction degree measured by the opposite electrode at the discharging time of the solution.

32. An apparatus in accordance with claim 28, further comprising a control means for controlling so that the open time of the above-described valve may become shorter as the PH for measuring with the PH meter becomes closer to a target valve.

33. An apparatus in accordance with claim 29, wherein an electrode provided within a cell is composed of a common electrode disposed in the upper, lower directions, an individual electrode disposed in a plurality of levels in given intervals in the upper, lower directions sidewards of the common electrode.

34. An apparatus in accordance with claim 30, wherein the one pair of opposite electrodes are oppositely disposed in the discharging opening of the cell.

35. An apparatus in accordance with claim 31, where the cell is composed of a separated liquid funnel.

36. An apparatus in accordance with claim 31, further comprising a valve for dripping acid an alkali into a cell, a PH meter for measuring the PH within the cell, a means for stirring the solution within the cell are provided, the PH being adapted to be measured after the decision of the separation of two layer by the deciding means after the stirring stop.

37. The automated synthesis apparatus in accordance with claims 1 or 2, wherein the respective means of the synthesis processing apparatus comprise:

a sample supply unit provided with;

a plurality of storing containers for storing raw materials, reagents, solvents, pH adjusting liquids;

a means for automatically feeding the sample from storing cells to the storing containers, a volumetric tube and a sensor for measuring the samples to be transported from the storing containers;

a flow line for flowing operation from each of the storing container to another element of said synthesis processing apparatus, and an electromagnetic valve for opening and closing flow passages interposed in each flow line;

a reaction unit composed of;

a reaction vessel unit;

an extraction/dehydration unit a pH adjusting unit and a reaction unit, provided with a plurality of reaction vessels and pH adjusting vessels;

flow lines for feeding a sample of an optional storing container from among storing containers provided in the sample supply unit;

flow lines provided for circulating samples among the plurality of reaction vessels, and among these reaction vessels and pH compensating vessels;

extraction/separation funnels and dehydrating tubes provided for circulating samples through the flow lines among the respective vessels, a means for analyzing a reaction liquid connected through the respective reaction vessels and flow lines; and

electromagnetic valves for opening and closing the flow passages interposed in the respective flow lines;

a purifying unit comprising a purifier combined with a separation liquid unit and connected through the respective reaction vessels and flow lines provided in the reaction units, and to a fraction collector so as to feed an optional purified product collected in the fraction collector through the flow lines to the reaction vessels of the reaction units;

a temperature control unit provided with a means for circulating hot media or cold media to heat or cool the reaction vessels and a separate heater for also heating the reaction vessels;

a washing unit for transporting the washing liquid to the reaction vessels and quantifying devices.

7. A method for automatically controlling the operation of an automated synthesis apparatus which includes:

a means for shifting contents of at least one container selected from a plurality of storing containers, including reaction vessels to another container;

a means for reacting the contents of selected reaction vessels;

a means for analyzing with analyzers at least one portion of the contents taken out of the reaction vessels;

a means for separating and purifying with purifiers at least one material from the contents of the reaction vessels; and

a means for restoring each of the means to their initial condition, said method comprising the steps of;

storing in advance a plurality of unit operating procedures, each of the operating unit procedures operating one of the means of the synthesis processing apparatus;

compiling at least one selected unit operating procedure to set up an operating procedure for synthesizing a specific target compounds;

selecting and connecting together each means of the synthesis processing apparatus in accordance with the compiled operating procedures to set up control procedures for operating all of the selected means of the synthesis processing apparatus in sequence; and

actuating the control procedure to operate each means of the synthesis processing apparatus for synthesizing the specific target compound.

8. The controlling method in accordance with claim 7, further comprising the steps of, in a unit operating procedure for operating a means for moving the contents to another container from one storing container and circulating the contents to the container:

feeding a required amount to one specific reaction vessel of the reaction unit from one specific storing container of the sample supply unit;

feeding an entire amount of samples from one specific storing container of the sample supply unit to one specific reaction vessel;

transporting the contents of one specific reaction vessel to another specific reaction vessel;

extraction/dehydration the contents of one specific reaction vessel and to transport an upper layer liquid to another specific reaction vessel;

extraction/dehydration of the contents of one specific reaction vessel and to transport a lower layer liquid to another specific reaction vessel, transporting the contents from one specific reaction vessel to the pH adjusting vessel;

transporting the contents of the pH adjusting vessel to one specific reaction vessel;

transporting the contents of a fraction tube to one specific reaction vessel;

transporting the contents of one specific reaction vessel to the container of the purifying unit;

transporting the contents of one specific reaction vessel to the extraction/separation funnel;

wasting the contents from the extraction/separation funnel;

transporting the contents of the storing container of the extraction/dehydration unit to the extraction/separation funnels for washing them;

transporting the contents of the extraction/separation funnels to the storing container;

transporting the contents of the extraction/separation funnels to two specific reaction vessels;

transporting the contents of the extraction/separation funnels to one specific reaction vessel;

transporting the contents of one specific reaction vessel to the storing container of the reaction analyzing unit; and

transporting the washing liquid to one specific reaction vessel through one specific quantifier device.

9. The controlling method in accordance with claim 7, comprising the steps of, in a unit operating procedure for operating a means for reacting the contents of the selected specific reaction vessel:

in starting the cooling of one specific contents in the reaction vessel;

completing the cooling of one specific contents in the reaction vessel;

effecting the concentration amount of one specific contents in the reaction vessel;

starting the stirring of one specific contents in the reaction vessel;

completing the stirring of one specific contents in the reaction vessel.

10. The controlling method in accordance with claim 7, comprising the step of, in a unit operating procedure for operating a means for automatically analyzing with an analyzer with one portion of the reactant taken out from the reaction vessel being selected:

turning on an analyzing HPLC switch;

turning off the analyzing HPLC switch;

sampling the samples of one specific reaction vessel to effect the analyzing operation with HPLC after dilution.

11. The controlling method in accordance with claim 7, further comprising the steps of, in a unit operating procedure for operating a means for separating and purifying a specific material from the contents within the reaction vessel by a separating and purifying device selecting a chromatocolumn to operate with a detector;

resetting the chromatocolumn and the detector; and

purifying samples to an HPLC from the storing container so as to effect a chromatographing operation.

12. The controlling method in accordance with claim 7, further comprising the steps of, in a unit operating procedure for operating a means for restoring the means of the automated synthesis apparatus to their initial conditions:

transporting a washing liquid to one specific reaction vessel through one specific quantifying device;

drying one specific reaction vessel;

said drying the flow lines.

13. The controlling method in accordance with claim 7, further comprising a step of including, in the unit operation procedure, a starting procedure of setting by inputting of the synthesis conditions, a sub-operation procedure for execution exclusive use.

14. The controlling method in accordance with claim 7, further comprising the steps of, in the effecting a synthesis procedure program:

inputting a program name;

selecting a start procedure for inputting synthesis conditions;

selecting a unit operating procedure; and

sequentially inputting a name of the unit operating procedure selected in accordance with an operation order so as to effect a combining operation.

15. The controlling method in accordance with claim 7, further comprising the step of interrupting the execution in accordance with the synthesis procedure program by an automatic synthesis controlling program in accordance with an interrupt program so that the driving of the synthesis processing apparatus is effected in accordance with the interruption program.

16. The controlling method in accordance with claim 15, further comprising the step of including, in the interrupt program:

a program for changing a time setting of a reaction, or changing a concentration of the synthesis procedure program;

a program arranged so that an analysis start and completion can be effected at an optional time;

a program for re-setting conditions at a purification time; and

a program adapted to change so that a determination so as to the completion of a reaction may be effected by an automatic analysis of a reaction condition, instead of a time setting.