Solid phase organic synthesis device with pressure-regulated manifold

• US 5,792,430 A
• Filed: 07/25/1997
• Issued: 08/11/1998
• Est. Priority Date: 08/12/1996
• Status: Expired due to Fees

• Current Assignee: Monsanto Technology LLC (Bayer AG)
• Original Assignee: Monsanto Company (Bayer AG)
• Inventors: Hamper, Bruce C.
• Primary Examiner(s): BHAT, NINA NMN
• Application Number:
  US08/900,120
• Time in Patent Office: 382 Days
• Field of Search: 422/131, 422/134, 422/138, 422/100, 422/102, 422/103, 422/116, 536/23.1
• US Class Current: 422/131
• 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 2219/00308 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 2219/00416 Vacuum
• CPC Class Codes: B01J 2219/00418 using pressure
• CPC Class Codes: B01J 2219/00423 using filtration, e.g. through porous frits
• CPC Class Codes: B01J 2219/00454 by chemical cleavage from the solid support
• CPC Class Codes: B01J 2219/00493 by sparging or bubbling with gases
• CPC Class Codes: B01J 2219/005 Beads
• 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: C40B 50/14 Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• CPC Class Codes: C40B 60/14 for creating libraries

Abstract

A solid phase organic synthesis device comprising a manifold and an optional heating block mounted to an upper surface of the manifold. The manifold includes an internal cavity and a first array of holes coupled to the internal cavity. The heating block includes a second array of holes vertically aligned with the corresponding holes of the first array. The first and second arrays of holes are adapted to accommodate flow-through reaction vessels. Each reaction vessel is secured in one of the holes of the first array and a vertically-aligned one of the holes of the second array. The interiors of the reaction vessels are in communication with the internal cavity of the manifold. The flow-through reaction vessels, which contain solid phase resins for solid phase organic synthesis, are controlled by regulating the pressure within the manifold. The manifold includes a pressure port coupled to both an inert gas source and a pressure control device, and a vacuum port coupled to a vacuum control device and a vacuum source. The pressure control device and the vacuum control device are easily operated to create a vacuum and varying degrees of positive pressure within the manifold, as required when carrying out an organic synthesis. A second manifold is mounted on the first manifold in the absence of the reaction vessels for supplying inert gas used to concentrate organic synthesis products.

Claims

1. A solid phase organic synthesis arrangement, comprising:

a manifold having a first array of holes opening into the interior of said manifold;

a plurality of flow-through reaction vessels having openings at the top and bottom and retained in respective ones of said holes of said first array, the interior of said reaction vessels being in communication with the interior of said manifold through the bottom of said reaction vessel, thereby permitting liquids introduced into said vessels to flow out the bottom of said vessels unless prevented from doing so; and

pressure-regulating means, coupled to said manifold, for regulating gas pressure within said manifold, said pressure-regulating means being capable of creating (a) a vacuum within said manifold for draining liquids contained in said reaction vessels, (b) a slight positive holding pressure relative to the pressure above said vessels within said manifold for preventing liquids from draining into said manifold from said reaction vessels and in contact with solid phase resins in said reaction vessels, and (c) a stronger positive pressure within said manifold for agitating the solid phase resins in said reaction vessels.

2. The arrangement of claim 1, wherein the pressure of (b) is within the range of about 0.05 to 0.2 psig.(0.34 to 1.38 kPa).

3. The arrangement of claim 1, wherein the pressure of (c) is within the range of about 0.2 to 1.0 psig. (1.38 to 6.9 kPa).

4. The arrangement of claim 1, wherein the flow-through reaction vessels have outlets communicating with the interior of said manifold with an internal diameter of about 0.005 to 0.1 in.(0.127 to 2.54 mm).

5. The arrangement of claim 1, wherein said pressure regulating means is capable of providing gas flow sufficient to maintain the positive pressures of (b) and (c).

6. The arrangement of claim 1, wherein the vacuum of (a) is within the range of about -10 to -30 in. Hg(0 to 508 torr).

7. The arrangement of claim 1, wherein said pressure-regulating means includes a pressure port communicating with the interior of the manifold and connected to a pressure control device and an inert gas source, and further includes a vacuum port communicating with the interior of the manifold and connected to a vacuum control device and a vacuum source.

8. The arrangement of claim 7, wherein said pressure control device is a manually operated three-way valve connected to said inert gas source, and said vacuum control device is an on/off valve connected to said vacuum source and wherein said on/off valve is opened and said three-way valve is closed to create said vacuum, wherein said on/off valve is closed, said three-way valve is opened and used to create said slight positive holding pressure, and wherein said on/off valve is closed, said three-way valve is opened and used to create said stronger positive pressure.

9. The arrangement of claim 7, wherein said pressure-regulating, means includes an electronic pressure control valve.

10. The arrangement of claim 7, wherein said pressure-regulating means includes an electronic vacuum control valve.

11. The arrangement of claim 1, further including a heating block mounted to an upper surface of said manifold, said heating block including a second array of holes vertically aligned with said corresponding holes of said first array, said reaction vessels passing through respective ones of said holes of said second array.

12. The arrangement of claim 11, wherein said heating block includes a main body and one or more feet extending downward from said main body, said main body being composed of a thermally conductive material and said feet being composed of a thermally nonconductive material, said feet resting o n said upper surface of said manifold and creating a gap between said manifold and said main body.

13. The arrangement of claim 12, wherein said heating block includes heating means for heating said main body to a temperature warmer than the ambient environment.

14. The arrangement of claim 13, wherein said heating means includes a heating pad mounted to said main body.

15. The arrangement of claim 1, wherein said manifold includes a box and a cover plate detachably connected to said box, said cover plate forming said first array of holes.

16. The arrangement of claim 15, wherein said box includes a bottom, a pair of opposing side walls, and a pair of opposing end walls, said side walls and said end walls extending upward from said bottom, and wherein said cover plate is disposed opposite to said bottom.

17. The arrangement of claim 1, further including a collection rack holding a plurality of collection vials and disposed within said manifold, said collection vials being located beneath respective ones of said reaction vessels.

18. The arrangement of claim 17, further comprising a second manifold mounted on said box in the absence of said flow-through reaction vessels for supplying gas to said collection vials.

19. A solid phase organic synthesis arrangement, comprising:

a box including a bottom, a pair of opposing side walls, and a pair of opposing end walls, said side walls and said end walls extending upward from said bottom, said end walls extending between said pair of side walls;

a cover plate detachably connected to said box, said cover plate being mounted to upper surfaces of said side walls and said end walls and disposed opposite to said bottom, said cover plate and said box forming a manifold, said cover plate including a first array of holes for retaining respective flow-through reaction vessels having openings at the top and bottom such that the interior of said vessels are in communication with the interior of said manifold through the bottom of said reaction vessels, thereby permitting liquids introduced into said vessels to flow out the bottom of said vessels unless prevented from doing so; and

pressure-regulating means, coupled to said manifold, for regulating gas pressure within said manifold, said pressure-regulating means being capable of creating a vacuum within said manifold for draining liquids contained in said reaction vessels and varying degrees of positive pressure within said manifold relative to the pressure above said vessels for preventing liquids from draining into said manifold and for agitating solid phase resins disposed in said reaction vessels.

20. The arrangement of claim 19, further including a heating block mounted to an upper surface of said cover plate, said heating block including a second array of holes vertically aligned with said corresponding holes of said first array for receiving said reaction vessels.

21. The arrangement of claim 19, further comprising a removable rack for collection vials for placement inside said box, the holes in said cover plate being aligned with the rack of vials for collecting products from the reaction vessels.

22. The arrangement of claim 21, further comprising a second manifold mounted on said box in the absence of said flow-through reaction vessels for supplying gas to said collection vials.

23. The arrangement of claim 19, wherein said positive pressure is within the range of about 0.05 to 1.0 psig.(0.34 to 6.9 kPa.).

24. The arrangement of claim 19, wherein said vacuum is within the range of about -10 to -30 in Hg(0 to 508 torr).

25. A method of operating a solid phase organic synthesis arrangement including a first manifold forming a first array of holes opening into an interior of said manifold;

a plurality of flow-through reaction vessels having openings at the top and bottom and retained in respective ones of said holes of said first array, the interior of said reaction vessels being in communication with the interior of said manifold through the bottom of said reaction vessels, thereby permitting liquids introduced into said vessels to flow out the bottom of said vessels unless prevented from doing so, said reaction vessels containing solid phase resins; and

pressure-regulating means, coupled to said manifold, for regulating gas pressure or vacuum within said manifold, comprising the steps of (a) adding liquid reagents to said reaction vessels and maintaining a slight positive holding pressure within said manifold relative to the pressure above said vessels, thereby keeping said reagents in contact with said solid phase resins; and

(b) applying a vacuum within said manifold, thereby drawing liquid reagents out of said reaction vessels, through said manifold, and out of said manifold.

26. The method of claim 25, further including steps of (c) washing said solid phase resins with wash solvents while maintaining a slight positive holding pressure within said manifold;

(d) applying a stronger positive pressure within said manifold, said stronger positive pressure agitating said solid phase resins; and

(e) applying a vacuum within said manifold, said vacuum drawing said wash solvents out of said reaction vessels, through said manifold, and out of said manifold.

27. The method of claim 26, further including the steps of (f) adding cleavage solution to said reaction vessels while maintaining a slight positive holding pressure within said manifold, said slight positive holding pressure keeping said cleavage solution in contact with said solid phase resins;

and (g) applying a vacuum within said manifold, said vacuum drawing said reaction products out of said reaction vessels, and into a set of collection vials.

28. The method of claim 27, further including the steps of (h) removing said reaction vessels and securing a second manifold to said first manifold;

and (i) supplying a stream of inert gas to said second manifold, passing said inert gas through said collection vials, and withdrawing inert gas from said first manifold.

29. The method of claim 28, further including the step of (j) passing said inert gas leaving said second manifold through a trap to condense and collect solvents evaporated from said collection vials.