Apparatus and method for multiple synthesis of organic compounds on polymer support

• US 5,614,608 A
• Filed: 01/20/1995
• Issued: 03/25/1997
• Est. Priority Date: 01/20/1995
• Status: Expired due to Fees

• Current Assignee: Aventis Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Original Assignee: Selectide Corp. (Sanofi )
• Inventors: Krchnak, Viktor, Lebl, Michal, Seligmann, Bruce
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US08/375,879
• Time in Patent Office: 795 Days
• Field of Search: 395/904, 395/906, 525/54.1, 525/54.11, 528/312, 528/328, 530/334, 530/810, 422/116, 935/88
• US Class Current: 530/334
• 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 2219/00288 in the shape of syringes
• CPC Class Codes: B01J 2219/0029 with pistons or plungers
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/00351 Means for dispensing and evacuation of reagents
• CPC Class Codes: B01J 2219/00353 Pumps
• 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 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• 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 2219/0072 Organic compounds
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B25J 9/1679 characterised by the tasks executed
• CPC Class Codes: C07K 1/045 using devices to improve synthesis, e.g. reactors, special vessels
• CPC Class Codes: C07K 1/047 Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C40B 40/10 Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G05B 2219/40101 : Generate concurrent tasks
• CPC Class Codes: G05B 2219/45092 : Analysing or chemical synthesis robot, moving samples from station to station
• CPC Class Codes: Y10S 706/906 : Process plant

Abstract

A solid phase synthesis system is provided by employing a fully automated robot that operates with a novel timing protocol for handling multiple synthetic tasks efficiently. The novel timing protocol is realized by performing steps in the synthesis cycles for different compounds, such as peptides, concurrently rather than on a sequential basis.

Claims

1. A system for the solid phase synthesis of multiple species of organic compounds each formed by repeated synthetic cycles of synthetic steps, said system comprising:

a computer for processing a program of instructions correlated to predetermined synthetic cycles for the synthesis of each of said multiple species;

an automated robot responsive to said computer, said automated robot operative to cause said synthetic steps to be performed in accordance with the synthetic cycles of each of said multiple species; and

a timing protocol, implemented by said program of instructions and executed by said computer, for directing synthetic steps of at least two different species to be performed concurrently, said timing protocol determining if the time for a synthetic step in the synthetic cycle of one of said at least two different species is sufficient for initiating a synthetic step in the synthetic cycle of another of said at least two different species.

2. The system of claim 1 wherein each of said species has an associated sequence specific timing protocol, the compilation of all sequence specific timing protocols of species currently under synthesis being a cumulative remaining timing protocol, said system further including means for determining whether there is a timing conflict between the sequence specific timing protocol of a new desired species and the cumulative remaining timing protocol.

3. The system of claim 1 wherein said synthetic steps include the steps of washing, adding deprotection reagents, deprotection, adding coupling reagents and coupling.

4. The system of claim 1 wherein said synthetic steps include active and passive synthetic steps, said timing protocol directing said active steps within a first synthesis of a first species to be performed concurrently with passive steps within a second synthesis of a second species.

5. The system of claim 1 wherein said organic compounds include peptides.

6. The system of claim 1 further comprising:

a first set of a plurality of syringes, each syringe containing resin for repeatably coupling compounds to a solid support so as to synthesize a first species; and

a second set of a plurality of syringes, each syringe containing a desired compound that is to be coupled to the solid support during one of said synthetic cycles.

7. The system of claim 6 where said compound that is to be coupled is an amino acid for the synthesis of a peptide.

8. The system of claim 7 wherein said solid phase synthesis is a Merrifield solid phase peptide synthesis.

9. The system of claim 6 wherein said automated robot includes a gripper arm responsive to said computer, said gripper arm selectively positioning and manipulating syringes from said first and second sets of a plurality of syringes to thereby aspirate or dispense solvents and reagents required within said synthetic cycles.

10. The system of claim 1 further comprising a database containing parameter variables required for the synthesis of said multiple species of organic compounds, said database including the characteristic sequence of the repeated synthetic cycles for each of said multiple species.

11. A system for the solid phase synthesis of multiple peptides each formed by repeated synthetic cycles of synthetic steps, said system comprising:

a first set of syringes each holding a solid support;

a second set of syringes each holding a desired amino acid, said first set of syringes serving as the reaction vessels for coupling desired amino acids from said second set of syringes to the solid supports;

a computer for processing a program of instructions correlated to predetermined synthetic cycles for the synthesis of multiple peptides; and

an automated robot responsive to said computer, said automated robot operatively coupled to said first and second sets of syringes for aspirating and dispensing reagents so as to cause said repeated synthetic cycles to be performed in accordance with a desired peptide synthesis to thereby repeatably couple a desired amino acid to a solid support, said repeated [synthesis]synthetic cycles including the synthetic steps of washing, adding deprotection reagents, deprotection, adding coupling reagents and coupling,

said repeated synthetic cycles performed in accordance with a timing protocol wherein said washing, adding deprotection reagents or adding coupling reagents is performed concurrently with said deprotection or coupling for different peptide syntheses.

12. The system of claim 11 wherein said first set of syringes is made of polypropylene.

13. The system of claim 11 wherein each of said first set of syringes includes a solid phase retaining device.

14. The system of claim 13 wherein said solid phase retaining device is a frit.

15. The system of claim 11 wherein said solid support comprises a resin selected from the group consisting of polystyrene and polyethylene glycol.

16. The system of claim 11 where said automated robot includes an arm operatively connected to said robot so as to manipulate each of said first and second sets of syringes.

17. The system of claim 16 wherein said first and second sets of syringes each includes a plunger operatively coupled thereto, said plunger movable by said arm of said automated robot to thereby aspirate or dispense reagents.

18. The system of claim 17 wherein the content amount of reagents in each of said syringes is determined by the plunger position of the corresponding syringe.

19. The system of claim 11 further including an optical sensor responsive to the movement of said first and second sets of syringes, said optical sensor confirming the positioning of said first and second sets of syringes.

20. The system of claim 11 wherein said synthesis of peptides employs Fmoc/tBu chemistry.

21. The system of claim 11 further comprising piston pumps and delivery cups, said piston pumps delivering solvents and reagents to said delivery cups from which said first and second sets of syringes dispense or aspirate said solvents or reagents.

22. The system of claim 11 further including a database containing parameter variables required for the synthesis of the multiple peptides.

23. A process for the solid phase automated synthesis of multiple species of organic compounds formed by repeated synthetic cycles of synthetic steps, said process comprising the steps of:

a) initiating a synthetic step in a synthetic cycle of a species;

b) determining if the time for said synthetic step of step a) is sufficient for initiating a synthetic step in the synthetic cycle of a different species, and if so,

c) initiating a synthetic step in the synthetic cycle of said different species; and

d) repeating steps a), b) and c) until said multiple species are synthesized.

24. The process of claim 23 wherein said synthetic steps include washing, deprotection and coupling for the synthesis of multiple peptides.

25. The process of claim 24 wherein said deprotection and coupling are performed in a plurality of syringes which serve as reaction vessels.

26. A process for the automated solid phase synthesis of multiple peptides formed by repeated cycles of washing, adding deprotection reagents, deprotection, adding coupling reagents and coupling so as to repeatably couple amino acids to a solid support, said process comprising the steps of:

a) filling a first set of syringes, each with a resin solid support;

b) filling a second set of syringes, each with a desired amino acid;

d) washing one of said first set of syringes with a first solution;

e) adding deprotection solution to the syringe of step d) to initiate deprotection;

f) while deprotection of step e) is proceeding repeating steps d) and e) if the time for performing those steps is less than the time required for deprotection, otherwise proceeding with step g);

g) adding coupling solution to the syringe of step d) to initiate coupling to thereby couple a desired amino acid to the solid support; and

h) while coupling of step g) is proceeding repeating steps f) and g) if the time for performing those steps is less than the time for coupling, otherwise proceeding with steps d) and e) until the time for coupling expires.

27. The process of claim 26 wherein steps a) through h) are repeated until a peptide is synthesized.

28. The process of claim 26 further comprising the step of washing each of said first set of syringes of step d) prior to adding coupling solution.

29. The process of claim 26 wherein the system is automated through the use of a robot, said robot adding coupling and deprotection solution by manipulating the syringes so as to aspirate and dispense reagents.

30. The process of claim 26 wherein the first solution is dimethylformamide.

31. The process of claim 26 wherein the deprotection solution is piperidine/DMF.

32. The process of claim 26 wherein the coupling solution is a solution of DIC/HOBt.

33. The process of claim 26 further comprising the step of interactively prompting a user for parameter variables thereby forming a database required for the synthesis of the multiple peptides, said database including the characteristic amino acid sequence of each of the multiple peptides.

34. The process of claim 26 further comprising the step of adding or deleting peptide sequences to a list of peptides to be synthesized.

35. A process for the solid phase automated synthesis of multiple species of organic compounds formed by repeated synthetic cycles of synthetic steps, said process comprising the steps of:

a) determining a sequence specific timing protocol associated with a desired species to be synthesized, said sequence specific timing protocol including when each synthetic step for the desired species occurs temporally;

b) determining the cumulative remaining timing protocol of species currently under synthesis, said cumulative remaining timing protocol including when each synthetic step for the species currently under synthesis occurs temporally; and

c) determining whether a timing conflict exists between said sequence specific timing protocol and said cumulative remaining timing protocol, a timing conflict occurring when one synthetic step for the desired species to be synthesized cannot be performed concurrently with the synthetic steps of species currently under synthesis.

36. The process of claim 35 further comprising the step of time shifting the synthesis initiation of the desired species to be synthesized so as to resolve the time conflict.

37. The process of claim 35 wherein a time conflict occurs when an active synthetic step of the desired species to be synthesized is temporally coincident with any active synthetic steps for the species currently under synthesis.

38. The process of claim 35 wherein said organic compounds includes peptides.

39. The process of claim 35 further comprising the step of entering parameter variables required for the synthesis of the organic compounds.