Sequential reaction system

• US 7,413,714 B1
• Filed: 07/16/2000
• Issued: 08/19/2008
• Est. Priority Date: 07/16/2000
• Status: Expired due to Fees

• Current Assignee: YMC Co., Ltd. (YMC Investment KK)
• Original Assignee: YMC Co., Ltd. (YMC Investment KK)
• Inventors: Golbig, Klaus, Taghavi-Moghadam, Shahriyar, Hohmann, Michael, Oberbeck, Andreas, Schwalbe, Thomas
• Primary Examiner(s): Warden; Jill
• Assistant Examiner(s): LEVKOVICH, NATALIA A
• Application Number:
  US09/617,068
• Time in Patent Office: 2,956 Days
• Field of Search: 422/130, 422/62, 422/109, 436/50, 436/55, 700/266, 700/274
• US Class Current: 422/130
• 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 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/00337 Valves
• CPC Class Codes: B01J 2219/00389 Feeding through valves
• CPC Class Codes: B01J 2219/00495 Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00686 Automatic
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00704 integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: C07C 233/00 Carboxylic acid amides
• CPC Class Codes: C40B 40/04 Libraries containing only organic compounds
• CPC Class Codes: C40B 50/08 Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: Y10T 436/115831 Condition or time responsive
• CPC Class Codes: Y10T 436/12 Condition responsive control

Abstract

An automated sequential reaction system that can be used to either sequentially produce a plurality of different products each requiring a single reaction, or to produce a desired product that requires a series of sequential reactions. A system controller controls an automated reactant supply, a solvent supply, a reaction module, a detector, and a product collector. Prior to initiating any reaction, the system is flushed with solvent and a heat exchanger supplies the reaction module with a temperature-conditioned fluid to maintain the reaction module at a desired temperature. For single reactions, a plurality of reactants are injected into a chemical reactor included in the reaction module. As fluid exits the chemical reactor, the detector determines if the fluid is a desired chemical product or solvent, and routes the fluid to the appropriate receptacle. Once a predetermined volume of a desired product is obtained, the system is flushed with solvent, and a different set of reactants are injected into the chemical reactor to produce the next desired product. The process is repeated until a substance library of the desired products is obtained. For products requiring sequential reaction steps, either a plurality of reactors are employed, or an intermediate product produced by a previous reaction is reintroduced into the reaction module with an appropriate reactant to complete the next sequential reaction.

Claims

1. An automated sequential reaction system for automatically and sequentially producing a substance library of different desired chemical products from a plurality of reactants in accord with a programmed series of steps, comprising:

(a) a first automated reactant supply comprising a plurality of separate reactant chambers, each adapted to be filled with a different reactant;

(b) a first supply valve that is automatically actuatable and is connected to the first automated reactant supply to select a desired first reactant from among the plurality of separate reactant chambers;

(c) a solvent supply, said solvent supply being configured to contain a solvent for flushing said automated sequential reaction system;

(d) a reaction module coupled in fluid communication with said first supply valve, such that a reactant chamber selected from within said automated first reactant supply by the first supply valve is placed in fluid communication with said reaction module, said reaction module including a general purpose chemical reactor that is operable to produce the substance library of different desired chemical products from the plurality of reactants;

(e) an output valve that is automatically actuatable and is coupled in fluid communication with the reaction module to receive a desired chemical product, said desired chemical product contributing to the substance library of different desired chemical products;

(f) an automated product collector in fluid communication with said output valve to receive the desired chemical product and comprising a plurality of product chambers, each product chamber being adapted to be filled with a different desired product to produce the substance library of different desired chemical products; and

(g) a system controller controllably connected to the first automated reactant supply, the first supply valve, and the automated product collector, said system controller being programmed to monitor and control production of the plurality of desired chemical products by the automated sequential reaction system, the system controller being configured to operate the automated sequential reactant system as required to produce the substance library of different desired chemical products, the system controller implementing the steps of;

(i) controlling the first automated reactant supply and the first supply valve to introduce each reactant required to produce the substance library of different desired chemical products in a desired order; and

(ii) controlling the solvent supply to flush the general purpose reactor with the solvent as required, such that while the automated sequential reaction system is operational a fluid discharged from the reaction module alternates between;

(A) one of the different desired chemical products; and

(B) the solvent and any residual chemical product that is flushed from the reactor by the solvent.

2. The automated sequential reaction system of claim 1, wherein said solvent supply is selectively placed into fluid communication with the reaction module by the first supply valve under control of the system controller, to enable a solvent to flow from said solvent supply into said reaction module.

3. The automated sequential reaction system of claim 2, wherein said automated product collector further comprises a spent solvent reservoir, said spent solvent reservoir being adapted to contain a spent solvent that has been used to flush said sequential reaction system, said spent solvent reservoir being selectively placed into fluid communication with the reaction module by the output valve under control of said system controller, to enable a spent solvent to flow from the reaction module into said spent solvent reservoir.

4. The automated sequential reaction system of claim 1, wherein the solvent supply is part of the first automated reactant supply.

5. The automated sequential reaction system of claim 1, further comprising an automated detector disposed between the output valve and the reaction module and coupled to the system controller, said automated detector providing an output signal to the system controller that is indicative of whether a spent solvent or a desired chemical product is flowing from the reaction module, said system controller responding to the output signal to actuate the output valve to:

(a) selectively couple the reaction module in fluid communication with the automated product collector if the output signal indicates that a desired product is flowing from the reaction module; and

(b) selectively couple the reaction module in fluid communication with the spent solvent reservoir if the output signal indicates that a spent solvent is flowing from the reaction module.

6. The automated sequential reaction system of claim 1, further comprising a heat exchanger controllably connected to said system controller, said heat exchanger being configured to enable the system controller to control a temperature within said reaction module.

7. The automated sequential reaction system of claim 6, wherein said heat exchanger is disposed within said reaction module.

8. The automated sequential reaction system of claim 1, further comprising a pump having an inlet in fluid communication with said supply valve, and an outlet coupled in fluid communication with an inlet to the chemical reactor, said pump being controllably connected to said system controller to enable control of a flow rate of a first desired reactant into the chemical reactor.

9. The automated sequential reaction system of claim 1, wherein the reaction module includes a residence time chamber in fluid communication with an outlet of the chemical reactor, said residence time chamber providing additional time for a desired chemical product to be produced and having an outlet coupled in fluid communication with the output valve.

10. The automated sequential reaction system of claim 1, wherein said chemical reactor comprises a microreactor.

11. The automated sequential reaction system of claim 1, wherein said system controller includes a memory, a processor, and a user interface, said memory storing machine instructions that define the automated sequence of steps and which are executed by the processor to effect automatic control of the automated sequential reaction system.

12. The automated sequential reaction system of claim 8, wherein said outlet valve comprises a proportional valve configured to act as a throttle to enable a pressure along a reaction path to be selectively varied.

13. The automated sequential reaction system of claim 1, further comprising a second supply valve, and a second automated reactant supply, said second automated reactant supply comprising a plurality of separate reactant chambers, each adapted to be filled with a different reactant, said second supply valve being automatically actuatable and connected to the second automated reactant supply to select a second desired reactant from among the plurality of separate reactant chambers included therein under control of said system controller, said first desired reactant and said second desired reactant being supplied to the reaction module to produce the desired product.

14. An automated sequential reaction system for sequentially producing a substance library of a plurality of different chemical products using selected desired reactants from among a plurality of different reactants, comprising:

(a) a first automated fluid supply comprising a plurality of first separately addressable volumes that are selectively coupled in fluid communication with a first outlet, each volume being adapted to contain a different reactant;

(b) a second automated fluid supply comprising a plurality of second separately addressable volumes that are selectively coupled in fluid communication with a second outlet, each volume being adapted to contain a different reactant;

(c) a chemical reactor in fluid communication with said first outlet to receive a first desired reactant therefrom and with said second outlet to receive a second desired reactant therefrom, said chemical reactor being generally configured for sequentially producing the plurality of different chemical products by reacting successive different first and second desired reactants;

(d) a solvent supply adapted to contain a solvent and selectively provide the solvent to the chemical reactor for flushing the chemical reactor after each of the plurality of different chemical products has been produced thereby;

(e) an automated fluid collector comprising a plurality of separate fluid volumes, each fluid volume being selectively coupled to the chemical reactor to receive a different chemical product therefrom;

(f) a spent solvent reservoir that is selectively coupled in fluid communication with the chemical reactor, to receive a spent solvent that was used for flushing the chemical reactor after each different desired chemical product has been produced thereby; and

(g) a system controller controllably connected to the first automated fluid supply, the second automated fluid supply, the solvent supply, the chemical reactor, the spent solvent reservoir, and the automated fluid collector, said system controller being programmed to operate the automated sequential reactant system as required to produce the substance library of different desired chemical products, the system controller implementing the steps of;

(i) controlling the first automated reactant supply, the first supply valve, the second automated reactant supply, and the second supply valve to introduce each reactant required to produce the substance library of different desired chemical products in a desired order; and

(ii) controlling the solvent supply to flush the chemical reactor with the solvent as required, such that while the automated sequential reaction system is operational, a fluid discharged from the reaction module comprises either one of the different desired chemical products or the solvent along with any residual chemical product that is flushed from the reactor by the solvent.

15. The automated sequential reaction system of claim 14, further comprising a pump in fluid communication with said first outlet of said first fluid supply, with said second outlet of said second fluid supply, and with said chemical reactor, said pump being controllably connected to said system controller, which controls a flow rate of the first and second desired reactants through said automated sequential reaction system with the pump.

16. The automated sequential reaction system of claim 14, further comprising a residence time chamber in fluid communication with an outlet of said chemical reactor, said residence time chamber providing additional time for a chemical product to be produced and having an outlet coupled in fluid communication with the automated fluid collector and the spent solvent reservoir.

17. The automated sequential reaction system of claim 14, further comprising a detector in fluid communication with an outlet of said reactor, said detector producing a signal indicative of the type of fluid being discharged, said detector being controllably connected to said system controller, said system controller directing a spent solvent to said spent solvent reservoir and a desired chemical product to said automated fluid collector.

18. The automated sequential reaction system of claim 14, further comprising a heat exchanger controllably connected to said system controller, said heat exchanger being configured to enable the system controller to control a temperature within said chemical reactor.

19. An automated sequential reaction system for automatically and sequentially producing a substance library of different desired chemical products from a plurality of reactants in accord with a programmed series of steps, comprising:

(a) a first automated reactant supply comprising a plurality of separate reactant chambers, each adapted to be filled with a different reactant;

(b) a first supply valve that is automatically actuatable and is connected to the first automated reactant supply to select a first desired reactant from among the plurality of separate reactant chambers;

(c) a reaction module coupled in fluid communication with said first supply valve, such that a reactant chamber selected from within said automated reactant supply by the first supply valve is placed in fluid communication with said reaction module, said reaction module including a general purpose chemical reactor that is operable to produce the substance library of different desired chemical products from the plurality of reactants;

(d) an output valve that is automatically actuatable and is coupled in fluid communication with the reaction module to receive a desired chemical product, said desired chemical product contributing to the substance library of different desired chemical products;

(e) an automated product collector in fluid communication with said output valve to receive the desired chemical product and comprising a plurality of product chambers, each product chamber being adapted to be filled with a different desired product to produce the substance library of different desired chemical products;

(f) a system controller controllably connected to the first automated reactant supply, the first supply valve, the reaction module, and the automated product collector, said system controller being programmed to monitor and control production of the plurality of desired chemical products by the automated sequential reaction system, including controlling the first supply valve to select the first desired reactant, and controlling the output valve to select a product chamber into which the desired product is directed; and

(g) an automated detector disposed between the output valve and the reaction module and coupled to the system controller, said automated detector providing an output signal to the system controller that is indicative of whether a spent solvent or a desired chemical product is flowing from the reaction module, said system controller responding to the output signal to actuate the output valve to;

(i) selectively couple the reaction module in fluid communication with the automated product collector if the output signal indicates that a desired product is flowing from the reaction module; and

(ii) selectively couple the reaction module in fluid communication with a spent solvent reservoir if the output signal indicates that a spent solvent is flowing from the reaction module.

20. An automated sequential reaction system for automatically and sequentially producing a substance library of different desired chemical products from a plurality of reactants in accord with a programmed series of steps, comprising:

(a) a reactor configured to generate a desired chemical product from at least one reactant;

(b) a first reactant delivery structure configured to selectively deliver one of a plurality of different first reactants to the reactor;

(c) a solvent delivery structure configured to selectively deliver a solvent to the reactor, to enable the reactor to be flushed with the solvent; and

(d) a system controller controllably connected to said first reactant delivery structure and said solvent delivery structure, the system controller being configured to operate the automated sequential reactant system as required to produce the substance library of different desired chemical products, the system controller implementing the steps of;

(i) controlling the first reactant delivery structure to introduce a reactant required to produce a first desired product into the reactor for a period of time sufficient to produce a desired quantity of the first desired product;

(ii) controlling the solvent delivery structure to flush the reactor with the solvent after the desired quantity of the first desired product has been produced; and

(iii) repeating steps (i) and (ii) for each additional reactant required to produce an additional desired product, such that a volume of solvent separates each different desired product discharged from the reactor to produce the substance library of different desired chemical products, such that a flow of fluid discharged from the reactor comprises different desired chemical products separated by the solvent.

21. An automated sequential reaction system for automatically and sequentially producing a substance library of different desired chemical products from a plurality of reactants in accord with a programmed series of steps, comprising:

(a) a reactor configured to generate a desired chemical product from at least one reactant;

(b) a first reactant delivery structure configured to selectively deliver one of a plurality of different first reactants to the reactor;

(c) a solvent delivery structure configured to selectively deliver a solvent to the reactor, to enable the reactor to be flushed with the solvent;

(d) an output valve that is automatically actuatable and is coupled in fluid communication with the reactor to receive a fluid being discharged from the reactor;

(e) an automated detector disposed between the output valve and the reactor, said automated detector providing an output signal that is indicative of whether the fluid being discharged from the reactor comprises the solvent; and

(f) a system controller controllably connected to said first reactant delivery structure, said solvent delivery structure, said output valve, and said automated detector, the system controller being configured to operate the automated sequential reactant system as required to produce the substance library of different desired chemical products, the system controller implementing the steps of;

(i) controlling the first reactant delivery structure to introduce into the reactor each reactant required to produce the substance library of different desired chemical products in a desired order;

(ii) controlling the solvent delivery structure to flush the reactor with the solvent as required; and

(iii) controlling the state of the output valve based on the signal provided by the automated detector, such that when the signal from the automated detector indicates that a solvent is being discharged from the reactor module, the output valve is placed in fluid communication with the spent solvent collection volume, and when the signal from the automated detector indicates that a solvent is not being discharged from the reactor, the output valve is placed in fluid communication with the automated product collectors