Parallel reactor with internal sensing and method of using same

• US 6,924,149 B2
• Filed: 08/28/2002
• Issued: 08/02/2005
• Est. Priority Date: 08/13/1998
• Status: Expired due to Term

• Current Assignee: Freeslate Inc. (Unchained Labs Inc.)
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: Van Beek, Johannes A. M., Turner, Howard, Dales, G. Cameron, VanErden, Lynn, Rust, William C., Hajduk, Damian A., Nielsen, Ralph B.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Handy, Dwayne K
• Application Number:
  US10/229,424
• Publication Number:
  US 20030157721A1
• Time in Patent Office: 1,070 Days
• Field of Search: 422/99, 422/102, 422/105, 422/112, 422/129, 422/130, 422/131, 436/34, 436/37, 436/148, 436/174, 436/180, 436/181
• US Class Current: 436/148
• CPC Class Codes: B01F 33/452 using independent floating stirring elements
• CPC Class Codes: B01F 33/453 using supported or suspended stirring elements
• CPC Class Codes: B01F 35/212 of the driving system data, e.g. torque, speed or power data
• CPC Class Codes: B01F 35/213 of the properties of the mixtures, e.g. temperature, density or colour
• CPC Class Codes: B01F 35/2136 Viscosity
• CPC Class Codes: B01J 19/0006 Controlling or regulating processes controlling or regulating in general G05
• CPC Class Codes: B01J 19/0013 Controlling the temperature of the process
• CPC Class Codes: B01J 19/004 Multifunctional apparatus for automatic manufacturing of various chemical products sequential reactions B01J19/0046
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00029 Batch processes
• CPC Class Codes: B01J 2219/00162 controlling the pressure
• CPC Class Codes: B01J 2219/002 inside the reactor
• CPC Class Codes: B01J 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/0031 the racks or blocks being mounted in stacked arrangements
• CPC Class Codes: B01J 2219/00333 Closures attached to the reactor vessels
• CPC Class Codes: B01J 2219/00335 Septa
• CPC Class Codes: B01J 2219/00351 Means for dispensing and evacuation of reagents
• CPC Class Codes: B01J 2219/00367 capillary
• CPC Class Codes: B01J 2219/00373 Hollow needles
• CPC Class Codes: B01J 2219/00389 : Feeding through valves
• CPC Class Codes: B01J 2219/00418 : using pressure
• CPC Class Codes: B01J 2219/00477 : Means for pressurising the reaction vessels
• CPC Class Codes: B01J 2219/00481 : by the use of moving stirrers within the reaction vessels
• CPC Class Codes: B01J 2219/00495 : Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/00585 : Parallel processes
• CPC Class Codes: B01J 2219/0059 : Sequential processes
• CPC Class Codes: B01J 2219/00596 : Solid-phase processes
• CPC Class Codes: B01J 2219/00601 : High-pressure processes
• CPC Class Codes: B01J 2219/00686 : Automatic
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00691 : using robots
• CPC Class Codes: B01J 2219/00695 : Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00698 : Measurement and control of process parameters
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00704 : integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/0072 : Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00736 : Non-biologic macromolecules, e.g. polymeric compounds
• CPC Class Codes: B01J 2219/00738 : Organic catalysts
• CPC Class Codes: B01J 2219/00745 : Inorganic compounds
• CPC Class Codes: B01L 2200/026 : Fluid interfacing between devices or objects, e.g. connectors, inlet details
• CPC Class Codes: B01L 2300/049 : Valves integrated in closure
• CPC Class Codes: B01L 2300/06 : Auxiliary integrated devices, integrated components
• CPC Class Codes: B01L 2300/0627 : Sensor or part of a sensor is integrated
• CPC Class Codes: B01L 2300/14 : Means for pressure control
• CPC Class Codes: B01L 2300/1805 : Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
• CPC Class Codes: B01L 3/50851 : specially adapted for heating or cooling samples laboratory heating apparatus B01L7/00; incubators C12M
• CPC Class Codes: B01L 3/50853 : with covers or lids
• CPC Class Codes: B01L 7/54 : using spatial temperature gradients
• CPC Class Codes: C40B 40/14 : Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
• CPC Class Codes: C40B 40/18 : Libraries containing only inorganic compounds or inorganic materials
• CPC Class Codes: G01K 13/00 : Thermometers specially adapted for specific purposes
• CPC Class Codes: G01N 11/16 : by measuring damping effect upon oscillatory body
• CPC Class Codes: G01N 35/1079 : with means for piercing stoppers or septums
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/115831 : Condition or time responsive
• CPC Class Codes: Y10T 436/119163 : with aspirator of claimed structure
• CPC Class Codes: Y10T 436/12 : Condition responsive control
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/25875 : Gaseous sample or with change of physical state

Abstract

Devices and methods for controlling and monitoring the progress and properties of multiple reactions are disclosed. The method and apparatus are especially useful for synthesizing, screening, and characterizing combinatorial libraries, but also offer significant advantages over conventional experimental reactors as well. The apparatus generally includes multiple vessels for containing reaction mixtures, and systems for controlling the stirring rate and temperature of individual reaction mixtures or groups of reaction mixtures. In addition, the apparatus may include provisions for independently controlling pressure in each vessel, and a system for injecting liquids into the vessels at a pressure different than ambient pressure. In situ monitoring of individual reaction mixtures provides feedback for process controllers, and also provides data for determining reaction rates, product yields, and various properties of the reaction products, including viscosity and molecular weight Computer-based methods are disclosed for process monitoring and control, and for data display and analysis.

Claims

1. A method for monitoring the consumption of a gas-phase reactant in a catalyzed liquid-phase reaction contained in a vessel by monitoring pressure changes in the vessel, the method comprising

loading the vessel with a liquid-phase reaction material,

introducing the gas-phase reactant into the vessel,

pressurizing the vessel,

allowing the gas-phase reactant and the liquid-phase reaction material in the pressurized vessel to reach equilibrium with respect to the concentration of the gas-phase reactant in the liquid-phase reaction material,

injecting a catalytic liquid containing a catalyst for reacting the gas-phase reactant into the pressurized vessel containing the gas-phase reactant in equilibrium with the liquid-phase reaction material to form a liquid-phase reaction mixture comprising the liquid-phase reaction material and the catalyst,

reacting the gas-phase reactant in the liquid-phase reaction mixture such that the pressure in the vessel decays as the gas-phase reactant is consumed,

sensing the pressure within the vessel,

introducing additional gas-phase reactant into the vessel when the pressure in the vessel has decayed to a predetermined lower pressure limit, P_L, to increase the pressure in the vessel,

discontinuing the introduction of additional gas-phase reactant into the vessel in response to the pressure in the vessel increasing to a predetermined upper pressure limit, P_H, and

recording the pressure change data.

2. The method as set forth in claim 1 wherein the vessel is pressurized to a pressure greater than about 10 psig.

3. The method as set forth in claim 1 wherein the difference between the predetermined upper pressure limit, P_H, and the predetermined lower pressure limit, P_L, is about 4 psig.

4. The method as set forth in claim 1 wherein the gas-phase reactant comprises a gaseous monomer, the liquid-phase reaction material comprises a solvent for the gaseous monomer and the gaseous monomer is catalytically polymerized in the liquid-phase reaction mixture.

5. The method as set forth in claim 1 wherein the gas-phase reactant comprises a gaseous monomer, the liquid-phase reaction material comprises a liquid monomer and the gaseous monomer and liquid monomer are catalytically co-polymerized in the liquid-phase reaction mixture.

26. The method as set forth in claim 1 further comprising sensing the temperature of the reaction mixture in the vessel.

27. The method as set forth in claim 26 further comprising determining pressure changes in the vessel resulting from variation in the temperature of the reaction mixture.

28. The method as set forth in claim 1 further comprising regulating the temperature of the reaction mixture in the vessel.

29. The method as set forth in claim 1 further comprising displaying on a monitor the pressure change data.

30. The method as set forth in claim 1 further comprising performing a calculation using the pressure change data to determine an experimental variable for the vessel.

31. The method as set forth in claim 30 further comprising displaying on a monitor the experimental variable calculated using the pressure change data.

32. The method as set forth in claim 30 wherein the experimental variable calculated using the pressure change data is the consumption rate of the gas phase reactant.

6. A method for parallel processing of a plurality of reaction mixtures contained in a plurality of vessels and for monitoring the consumption or production of a gas-phase component of the reaction mixtures by monitoring the pressure changes in the vessels, the method comprising

reacting the reaction mixtures in a plurality of vessels such that the pressure in the vessels changes as the gas-phase component of the reaction mixtures is consumed or produced,

sensing the pressure within the vessels,

passing the gas-phase component of the reaction mixture into or out of the vessels in response to the pressure sensed within the vessels, and

recording the pressure change data for each of the vessels.

7. The method as set forth in claim 6, wherein the gas-phase component of the reaction mixture is a gas-phase reactant such that the pressure in the vessels decays as the gas-phase reactant is consumed, additional gas-phase reactant being introduced into each of the vessels when the pressure sensed in the vessel has decayed to a predetermined lower pressure limit, P_L, to increase the pressure in the vessel, and the introduction of additional gas-phase reactant into each of the vessels being discontinued in response to the pressure sensed in the vessel increasing to a predetermined upper pressure limit, P_H.

8. The method as set forth in claim 7 wherein the reaction mixtures are catalyzed liquid-phase reaction mixtures, the method further comprising

loading the vessels with a liquid-phase reaction material,

introducing the gas-phase reactant into the vessels,

pressurizing the vessels,

allowing the gas-phase reactant and the liquid-phase reaction material in the pressurized vessels to reach equilibrium with respect to the concentration of the gas-phase reactant in the liquid-phase reaction material, and

injecting a catalytic liquid containing a catalyst for reacting the gas-phase reactant into the pressurized vessels containing the gas-phase reactant in equilibrium with the liquid-phase reaction material to form the catalyzed liquid-phase reaction mixtures comprising the liquid-phase reaction material and the catalyst.

9. The method as set forth in claim 8 wherein the gas-phase reactant comprises a gaseous monomer, the liquid-phase reaction material comprises a solvent for the gaseous monomer and the gaseous monomer is catalytically polymerized in the liquid-phase reaction mixtures.

10. The method as set forth in claim 8 wherein the gas-phase reactant comprises a gaseous monomer, the liquid-phase reaction material comprises a liquid monomer and the gaseous monomer and liquid monomer are catalytically co-polymerized in the liquid-phase reaction mixtures.

11. The method as set forth in claim 7 wherein the vessels are pressurized to a pressure greater than about 10 psig.

12. The method as set forth in claim 7 wherein the difference between the predetermined upper pressure limit, P_H, and the predetermined lower pressure limit, P_L, is about 4 psig.

13. The method as set forth in claim 6 further comprising sensing the temperature of the reaction mixtures in the vessels.

14. The method as set forth in claim 13 further comprising determining pressure changes in the vessels resulting from variation in the temperature of the reaction mixtures.

15. The method as set forth in claim 6 further comprising regulating the temperature of the reaction mixtures in the vessels.

16. The method as set forth in claim 6 further comprising using the pressure change data for each of the vessels due to the consumption or production of the gas-phase component of the reaction mixtures to assess reaction kinetics and thereby screen the reaction mixtures.

17. The method as set forth in claim 16 wherein the reaction mixtures are catalyzed liquid-phase reaction mixtures and the pressure change data for each of the vessels due to the consumption or production of the gas-phase component of the reaction mixtures is used to assess the activity of the catalysts.

18. The method as set forth in claim 16 further comprising displaying on a monitor the pressure change data.

19. The method as set forth in claim 16 further comprising performing a calculation using the pressure change data to determine an experimental variable for one of the vessels.

20. The method as set forth in claim 19 further comprising displaying on a monitor the experimental variable calculated using the pressure change data.

21. The method as set forth in claim 19 wherein the experimental variable calculated using the pressure change data is the consumption or production rate of the gas-phase component of the reaction mixtures.

22. The method as set forth in claim 6 further comprising injecting a reaction material into one or more of the vessels while the pressure within the vessel is different from ambient pressure.

23. The method as set forth in claim 22 wherein the reaction material injected into one or more of the vessels is a quenching agent used to terminate the reaction in the vessel.

24. The method as set forth in claim 23 wherein the quenching agent is injected into one or more of the vessels once a specified conversion target has been attained.

25. The method as set forth in claim 24 wherein the liquid reaction mixtures are catalyzed liquid-phase reaction mixtures and the quenching agent injected into one or more of the vessels is a liquid-phase catalyst poison.