CH704658A1 - Synthesis of chemical compounds on a solid phase. - Google Patents

Synthesis of chemical compounds on a solid phase. Download PDF

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Publication number
CH704658A1
CH704658A1 CH00440/11A CH4402011A CH704658A1 CH 704658 A1 CH704658 A1 CH 704658A1 CH 00440/11 A CH00440/11 A CH 00440/11A CH 4402011 A CH4402011 A CH 4402011A CH 704658 A1 CH704658 A1 CH 704658A1
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CH
Switzerland
Prior art keywords
step
characterized
solid phase
method according
chemical compound
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CH00440/11A
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German (de)
Inventor
Hugo Dr Ziegler
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Hugo Dr Ziegler
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Hugo Dr Ziegler filed Critical Hugo Dr Ziegler
Priority to CH00440/11A priority Critical patent/CH704658A1/en
Publication of CH704658A1 publication Critical patent/CH704658A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/045General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers using devices to improve synthesis, e.g. reactors, special vessels

Abstract

The invention relates to a process for the preparation of a chemical compound, in particular a peptidic compound, e.g. an optionally substituted peptide, peptide derivative, peptide mimetic or protein, on the solid phase, an apparatus for carrying out the method, a solid phase for use in the method and apparatus, the use of this apparatus for carrying out the method and the use thereof solid phase in this method and in this device, characterized in that the basic structure of the solid phase is a band with linkers for a chemical reaction.

Description

The invention relates to a process for the preparation of a chemical compound, in particular a peptidic compound, for. A, optionally substituted, peptide, peptide derivative, peptide mimetics or protein, on the solid phase, an apparatus for performing this method, a solid phase for use in this method and apparatus, the use of this apparatus for performing this method, and the Use of this solid phase in this process and in this device.

Since Emil Fischer's groundbreaking discoveries at the beginning of the twentieth century, methods for the synthesis of peptidic compounds have been continually improved. Thus, selectively removable protecting groups have been developed, more efficient and useful coupling reagents provided, and total syntheses of biologically active peptidic compounds carried out. An overview of common chemical synthesis methods for peptidic compounds is provided, for example, by S. B. H. Kent, Ann. Rev. Biochem., 1988, 57, 957-989.

The introduction of insoluble resins ("Resins") as a synthesis aid (R. B. Merrifield, J. Am. Chem Soc, 1963, 85, 2149-2154) could simplify the synthesis process and increase the rate of synthesis. Such resins, typically organic polymers, e.g. B. in the form of small beads ("beads") are present in the solid phase chemistry, the so-called solid phase, with solid phase chemistry usually a chemical change in a heterogeneous medium, eg. B. on in a solvent-dispersed polymer beads, is understood. The synthesis objective is not to change the physical or chemical properties of the polymer itself, but on the polymer carrier a low molecular weight product, eg. As a peptidic compound to form. After his, often multi-step, synthesis is completed, the low molecular weight product bound to the carrier during the synthesis is cleaved again from the solid phase, may then optionally be subjected to purification and / or biologically, chemically and / or physically analyzed and then allowed to its further use. Previously, so during the synthesis of low molecular weight, z. Peptidic compound, the resin to which the growing compound is attached via a linker is filtered off after each coupling step and washed with solvent to remove excess reagents and by-products. This cleaning method for growing, z. As peptidic, compound was much easier and faster than the usual recrystallization of each of the products formed after the coupling steps products.

Further improvements in the synthesis process for peptidic compounds could be achieved by the inclusion of microwave technology. The first such synthesis in 1992, still carried out in a household microwave oven, yielded 2 to 4-fold reaction blending with 10% of available microwave power and a 55 ° C reaction temperature, but with poor reproducibility (typical for home appliances) , In the microwave-activated synthesis of the ACP peptide, a 3-fold reaction acceleration and a higher purity were found in 1997 at a reaction temperature of 60 ° C. In 2003, the Discover® microwave laboratory system (CEM Corporation, Matthews, NC, US) was introduced which, at an optimal reaction temperature of 60 ° C, allowed reproducible synthesis of pure peptidic compounds under 10 to 20-fold reaction acceleration. In the meantime, the use of microwave technology has become established, since under microwave action significantly shorter reaction times and, due to greatly reduced by-product formation, significantly simpler cleaning of the products result. In addition, often very difficult to synthesize and / or very long sequences are readily synthesized, which is likely to be due mainly to the elimination of the aggregation problem of hydrophobic peptide chains. So z. B. with microwave activation according to standard protocols (i.e., without optimization) in the synthesis of 42mers difficult to represent amyloid-beta 42 achieved a purity of 69% crude product, while without microwave activation results in a purity of only 10%. Despite thermal effects, microwave exposure suppresses racemization, and other classical side reactions, such as aspartimide formation, can be minimized by using microwave technology by optimizing the reaction conditions. Due to the increasing popularity of microwave technology, the protocols for syntheses are being further refined and optimized. Meanwhile, both manual and fully automated microwave laboratory systems are commercially available. For the manual synthesis of peptidic compounds finds z. For example, the "Discover SPS" (CEM Corporation) application, in which batch sizes of up to 3 mmol can be achieved. An average coupling cycle (including the washings) takes about 10 minutes with this system so that up to 6 amino acids can be coupled per hour. As the chain length increases, the use of an automated system, e.g. B. Liberty (CEM Corporation) makes sense, not least because of the higher reliability. With the Mars system (CEM Corporation), synthesis and cleavage can be performed in parallel on 96-well plates or analog devices.

These steady developments have improved the yields in the individual synthesis steps continuously, so that the synthesizable peptidic compounds can now have up to about 150 amino acid building blocks. However, as before, the synthesis of a peptidic compound in a larger amount, z. B. kilogram scale, due to the labor and time complexity of the synthesis process, especially the difficult purification of the products, a challenging and expensive endeavor. In particular, also has the microwave technology in their application during the synthesis of peptidic compounds on polymer beads the big disadvantage that the microwaves only a limited depth of penetration into the mass of the polymeric beads is available. However, the energy of the microwaves is greatest at the surface of the polymeric mass and decreases sharply with increasing penetration into deeper layers. Attempting to circumvent this effect by vigorous mechanical stirring of the bulk of the polymeric beads is unsuccessful because it partially destroys the solid phase. For this reason, so far only microwave synthesis systems are commercially available that are designed for a synthesis on a low millimole scale. These disadvantages are of particular importance in view of the increasing demand for peptidic compounds, but has z. For example, the number of peptidic compounds used as active ingredients for pharmaceutical or cosmetic applications has increased at an above-average rate in the past decade compared to the total number of active ingredients. Since numerous peptidic compounds are currently in the developmental stage, it can also be expected that the number and proportion of corresponding active substances will continue to increase and thus the demand for peptidic compounds will continue to grow.

To overcome these disadvantages, the invention provides a method and an apparatus available, which allow a chemical compound, in particular a peptidic compound, in a larger amount, for. B. kilogram scale, produce.

An object of the invention is a process for the preparation of a chemical compound on the solid phase, characterized in that a) a solid phase whose basic structure is a band with linkers for a chemical reaction, and n reaction chambers, where n is the total number of manufacturing steps taking place during the preparation of the chemical compound on the solid phase, are provided, b) then the strip is transported into a first reaction chamber, c) subsequently in this first reaction chamber the first of the production steps taking place during the production of the chemical compound on the solid phase is carried out, d) after completion of the manufacturing step of step c) of the process, the strip is transported to a next reaction chamber, e) subsequently in this next reaction chamber, the next of the manufacturing steps taking place during the preparation of the chemical compound on the solid phase, f) after completion of the manufacturing step of step e) of the process, the strip is again transported to a next reaction chamber, g) subsequently the production step of step e) of the process and the transport step of step f) of the process are repeated (n minus 3) times, with the proviso that the first step of step g) of the process is a production step with the further proviso that always a transport step from step g) of the process follows a production step of step g) of the process, and with the further proviso that the last production step of step g) of the process, which is the (n minus 1) - te is the production step which takes place during the production of the chemical compound on the solid phase, is the production step which directly precedes the production step of the removal of the chemical compound from the solid phase, h) then, in the last reaction chamber, the step of preparing the chemical compound from the solid phase is carried out, i) then the chemical compound from the last reaction chamber is isolated and j) if desired, subsequently converting a chemical compound obtainable in this way into another chemical compound, converting a chemical compound obtainable in salt form into the free form or into another salt form, converting a chemical compound obtainable in free form into a salt form and / or one so available chemical compound is separated in the form of a mixture of isomers in a special mixture of isomers or in a pure isomer.

According to particular embodiments of the inventive method, the linkers for a chemical reaction are either attached to the tape itself or they are on polymer beads (beads), which are on the band, preferably tightly packed next to each other, attached, wherein the Band either only on one side or on both sides carries linker.

The linker may be attached directly to the tape, but the surface is larger when using beads because of their Kugeiform, which advantageously leads to a higher loading density. In addition to the spherical shape, the beads may also have another suitable shape with a large surface, z. Be egg-shaped. As polymers for the beads, all polymers commonly used for this purpose are suitable.

According to particular embodiments of the inventive method, the tape is a polymer film, which consists of either a polymer other than, or preferably from the same polymer as, the polymer beads (beads).

As polymers for the polymer film, all polymers commonly used for this purpose are suitable.

According to particular embodiments of the process according to the invention, a production step of step c), step e) or step g) of the process is selected from the group consisting of a preparation step (eg an activation step), a coupling step, a work-up step and a cleaning step (eg, a washing step).

According to particular embodiments of the inventive method, a reaction chamber contains one or more than one agent which is selected from the group consisting of a solvent, a reagent and a synthesis aid.

As synthesis excipients z. As catalysts into consideration.

According to particular embodiments of the inventive method, one or more than one production step is carried out in a reaction chamber with stirring.

According to particular embodiments of the inventive method, one or more than one production step is carried out under microwave action, wherein in particular one or more than one preparation step is selected from the group consisting of a preparation step of stage c), stage e) or stage g) of the process, a coupling step of step c), step e) or step g) of the process and the cleavage step of step h) of the process.

The inventive method allows the microwaves to transfer their energy to all reaction centers, since the polymeric beads (beads) packed tightly arranged side by side are mounted on the belt. The microwave generator, z. As a magnetron, a klystron, a transistor, an electronic oscillator, a traveling wave tube or a diode, may be located inside or outside a reaction chamber.

According to particular embodiments of the process according to the invention, the preparation step of step c) of the process is the coupling step of a reagent to the linker.

According to particular embodiments of the inventive method, the production steps to be carried out in these reaction chambers are carried out simultaneously in two or more than two, in particular in all n, different reaction chambers.

According to particular embodiments of the inventive method, the chemical compound to be produced is a peptidic compound, in particular a compound selected from the group consisting of an optionally substituted peptide, an optionally substituted peptide derivative, an optionally substituted Peptidmimikum and an optionally substituted protein, in particular a peptide.

Another object of the invention is a device for carrying out the inventive method for producing a chemical compound on the solid phase, characterized in that the device is a solid phase whose basic structure is a band with linkers for a chemical reaction, n Reaction chambers, where n is the total number of manufacturing steps occurring during the preparation of the chemical compound on the solid phase, and contains a means for the transport of the solid phase through the n Reaktionskammem.

According to particular embodiments of the device according to the invention, this additionally contains an agent which makes it possible to carry out one or more than one preparation step with stirring, and / or an agent which makes it possible to carry out one or more production steps under microwave action.

Another object of the invention is a solid phase as defined above or in any one of claims 1 to 8.

Another object of the invention is a solid phase as defined in claim 23 for use in a method as defined in claims 1 to 19 or in a device as defined in claims 20 to 22.

Another object of the invention is the use of a device as defined above or in any one of claims 20 to 22 defined for carrying out a method as in claims 1 to 19.

Another object of the invention is the use of a solid phase as defined in claim 23 or claim 24 in a method as defined in claims 1 to 19 or in a device as defined in claims 20 to 22.

For the automation of synthesis and for the synthesis of larger amounts of the peptidic compound is crucial that the tape is continuously performed in uniform steps through the reaction chambers in which proceed at the respective tape sections required for the preparation of the compounds manufacturing steps.

The following example is illustrative of the invention and does not limit it.

example

For the first preparation step, a band covered with suitable linkers is introduced into a reaction chamber in which the reagent, e.g. B. dissolved in a solvent, is present. The reagent then undergoes a chemical reaction, optionally under microwave action, with the functional group of the linkers. If necessary, the reaction mixture can be stirred by means of a magnetic stirrer. The tape is then transported to a second chamber where it is washed and / or otherwise prepared for the next coupling step, e.g. B. freed of a protecting group and / or activated, is, depending on the synthesis protocol, one or more other chambers can be used. After transport into a next chamber, the next production step is then carried out, in which the next reagent is coupled to the intermediate bound to the linker, optionally again under microwave action. This procedure is repeated until the desired connection is established on the belt, always with one transport step following one production step. In the last reaction chamber, the desired compound is split off from the resin. Subsequently, the isolation of the compound and, optionally, one or more post-operations done.

Claims (26)

1. A process for preparing a chemical compound on the solid phase, characterized in that a) a solid phase whose basic structure is a band with linkers for a chemical reaction, and n reaction chambers, where n is the total number of manufacturing steps taking place during the preparation of the chemical compound on the solid phase, are provided, b) then the strip is transported into a first reaction chamber, c) subsequently in this first reaction chamber the first of the production steps taking place during the production of the chemical compound on the solid phase is carried out, d) after completion of the manufacturing step of step c) of the process, the strip is transported to a next reaction chamber, e) subsequently in this next reaction chamber, the next of the manufacturing steps taking place during the preparation of the chemical compound on the solid phase, f) after completion of the manufacturing step of step e) of the process, the strip is again transported to a next reaction chamber, g) subsequently the production step of step e) of the process and the transport step of step f) of the process are repeated (n minus 3) times, with the proviso that the first step of step g) of the process is a production step with the further proviso that always a transport step from step g) of the process follows a production step of step g) of the process, and with the further proviso that the last production step of step g) of the process, which is the (n minus 1) - te is the production step which takes place during the production of the chemical compound on the solid phase, is the production step which directly precedes the production step of the removal of the chemical compound from the solid phase, h) subsequently in the last reaction chamber the production step of the removal of the chemical compound from the solid phase is carried out, i) then the chemical compound from the last reaction chamber is isolated and j) if desired, subsequently converting a chemical compound obtainable in this way into another chemical compound, converting a chemical compound obtainable in salt form into the free form or into another salt form, converting a chemical compound obtainable in free form into a salt form and / or one so available chemical compound is separated in the form of a mixture of isomers in a special mixture of isomers or in a pure isomer.
2. The method according to claim 1, characterized in that the linkers are mounted on the tape itself.
3. The method according to claim 1, characterized in that the linkers are on polymer beads (beads) which are fixed on the belt.
4. The method according to claim 3, characterized in that the polymer beads (beads) are arranged tightly packed next to each other on the tape.
5. The method according to any one of claims 1 to 4, characterized in that the band consists of a polymer film.
6. The method according to claim 5, characterized in that the polymer beads (beads) and the Polymeifolie consist of the same polymer.
7. The method according to any one of claims 1 to 6, characterized in that the band carries on one side linker.
8. The method according to any one of claims 1 to 6, characterized in that the band carries linkers on both sides.
9. The method according to any one of claims 1 to 8, characterized in that a production step of step c), step e) or step g) of the method is selected from the group consisting of a preparation step, a coupling step, a work-up step and a purification step ,
10. The method according to any one of claims 1 to 9, characterized in that a reaction chamber contains one or more than one agent which is selected from the group consisting of a solvent, a reagent and a synthesis aid.
11. The method according to any one of claims 1 to 10, characterized in that one or more than one production step is carried out in a reaction chamber with stirring.
12. The method according to any one of claims 1 to 11, characterized in that one or more than one manufacturing step is carried out under microwave action.
13. The method according to claim 12, characterized in that one or more than one preparation step is selected from the group consisting of a preparation step of step c), step e) or step g) of the process, a coupling step of step c), step e) or step g) of the process and the cleavage step of step h) of the process.
14. The method according to any one of claims 1 to 13, characterized in that the production step of step c) of the method is the coupling step of a reagent to the linker.
15. The method according to any one of claims 1 to 14, characterized in that in two or more than two different reaction chambers to be carried out in these reaction chambers manufacturing steps are carried out simultaneously.
16. The method according to any one of claims 1 to 15, characterized in that in all n different reaction chambers, the manufacturing steps to be carried out in these reaction chambers are carried out simultaneously.
17. The method according to any one of claims 1 to 16, characterized in that the chemical compound is a peptidic compound.
18. The method according to claim 17, characterized in that the peptidic compound is selected from the group consisting of an optionally substituted peptide, an optionally substituted peptide derivative, an optionally substituted Peptidmimikum and an optionally substituted protein.
19. The method according to claim 17 or claim 18, characterized in that the peptidic compound is a peptide.
Device for carrying out a process as defined in claims 1 to 19 for the preparation of a chemical compound on the solid phase, characterized in that the device comprises a solid phase whose basic structure is a band with linkers for a chemical reaction, n reaction chambers where n is the total number of manufacturing steps carried out during the preparation of the chemical compound on the solid phase and contains a means for transporting the solid phase through the n reaction chambers.
21. A device according to claim 20, characterized in that it additionally contains an agent which makes it possible to carry out one or more than one preparation step with stirring.
22. Device according to claim 20 or claim 21, characterized in that it additionally contains an agent which makes it possible to perform one or more than one manufacturing step under microwave action.
23. Solid phase as defined in claims 1 to 8.
A solid phase as defined in claim 23 for use in a method as defined in claims 1 to 19 or in a device as defined in claims 20 to 22.
25. Use of a device as defined in claims 20 to 22 defined for carrying out a method as in claims 1 to 19.
Use of a solid phase as defined in claim 23 or claim 24 in a method as defined in claims 1 to 19 or in a device as defined in claims 20 to 22.
CH00440/11A 2011-03-16 2011-03-16 Synthesis of chemical compounds on a solid phase. CH704658A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CH00440/11A CH704658A1 (en) 2011-03-16 2011-03-16 Synthesis of chemical compounds on a solid phase.

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Application Number Priority Date Filing Date Title
CH00440/11A CH704658A1 (en) 2011-03-16 2011-03-16 Synthesis of chemical compounds on a solid phase.
PCT/EP2012/054600 WO2012123553A1 (en) 2011-03-16 2012-03-15 Synthesis of chemical compounds on a solid phase

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CH704658A1 true CH704658A1 (en) 2012-09-28

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4794150A (en) * 1987-03-11 1988-12-27 Samuel Steel Synthesis of peptide analogs
EP0385433A2 (en) * 1989-02-28 1990-09-05 Ceskoslovenska Akademie Ved Method and apparatus for the continuous polymer synthesis on a solid carrier
WO1995011748A1 (en) * 1993-10-28 1995-05-04 Beckman Instruments, Inc. Method and apparatus for creating biopolymer arrays on a solid support surface
WO2002051917A1 (en) * 2000-12-22 2002-07-04 Poly-An Gesellschaft zur Herstellung von Polymeren für spezielle Anwendungen und Analytik mbH Surface-functionalised carrier material, method for the production thereof and solid phase synthesis method
EP1923396A2 (en) * 2006-10-24 2008-05-21 CEM Corporation Microwave-Assisted Peptide Synthesis

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4794150A (en) * 1987-03-11 1988-12-27 Samuel Steel Synthesis of peptide analogs
EP0385433A2 (en) * 1989-02-28 1990-09-05 Ceskoslovenska Akademie Ved Method and apparatus for the continuous polymer synthesis on a solid carrier
WO1995011748A1 (en) * 1993-10-28 1995-05-04 Beckman Instruments, Inc. Method and apparatus for creating biopolymer arrays on a solid support surface
WO2002051917A1 (en) * 2000-12-22 2002-07-04 Poly-An Gesellschaft zur Herstellung von Polymeren für spezielle Anwendungen und Analytik mbH Surface-functionalised carrier material, method for the production thereof and solid phase synthesis method
EP1923396A2 (en) * 2006-10-24 2008-05-21 CEM Corporation Microwave-Assisted Peptide Synthesis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FRANK ET AL: "Spot-synthesis: an easy technique for the positionally addressable, parallel chemical synthesis on a membrane support", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 48, no. 42, 1 January 1992 (1992-01-01), pages 9217 - 9232, XP026636781, ISSN: 0040-4020, [retrieved on 19920101], DOI: 10.1016/S0040-4020(01)85612-X *

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