EP0971947A2 - Rink-chloride linker for solid phase organic synthesis of organic molecules - Google Patents
Rink-chloride linker for solid phase organic synthesis of organic moleculesInfo
- Publication number
- EP0971947A2 EP0971947A2 EP98913115A EP98913115A EP0971947A2 EP 0971947 A2 EP0971947 A2 EP 0971947A2 EP 98913115 A EP98913115 A EP 98913115A EP 98913115 A EP98913115 A EP 98913115A EP 0971947 A2 EP0971947 A2 EP 0971947A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- resin
- bound
- rink
- linker
- chloride
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 238000003786 synthesis reaction Methods 0.000 title claims description 20
- 239000007790 solid phase Substances 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 25
- 229920005989 resin Polymers 0.000 claims description 86
- 239000011347 resin Substances 0.000 claims description 86
- 239000012038 nucleophile Substances 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 30
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 230000008878 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 8
- 125000005647 linker group Chemical group 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 20
- 239000007787 solid Substances 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000011324 bead Substances 0.000 description 9
- 238000003776 cleavage reaction Methods 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000002952 polymeric resin Substances 0.000 description 6
- 229920003002 synthetic resin Polymers 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- -1 needles Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920005990 polystyrene resin Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/045—General 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
Definitions
- This invention relates to a novel linker for use in solid phase chemistry, its preparation and methods of use of the linker.
- the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks.
- the biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
- This invention relates to a novel solid phase Rink linker of formula (I), hereinafter referred to as a resin-bound Rink-chlo ⁇ de linker or a Rink-chlo ⁇ de linker
- a resin-bound Rink-chlo ⁇ de linker or a Rink-chlo ⁇ de linker This represents a significant improvement over the current use of the Rink- acid linker.
- the use of the known Rink-acid linker is limited to preparing amides and carboxyhc acids.
- the use of the instant improved Rink-chlo ⁇ de linker of formula (I) makes Rink technology available to a broad number of functional group attachments.
- Rink-chlo ⁇ de linker allows a very general and practical method for the attachment of amines, alcohols and thiols, including phenols and thiophenols to a solid support. Therefore, another aspect of the instant invention is in a method for making compounds by resin-bound synthesis using the Rink- chlo ⁇ de linker in solid phase synthesis. This method is applicable to making combinatorial libraries of compounds designed around a core molecular structure using known methods of solid phase combinatorial chemistry or multiple simultaneous synthesis ("parallel synthesis") The compounds or libraries of compounds made using this linker may be tested in biologically assays designed to test for a particular physical characteristic potentially useful in drug therapy
- polymeric resin support are used herein at all occurrences to mean a bead or other solid support such as beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, grafted co-poly beads, polyacryiamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-b ⁇ s-acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface.
- the solid support is suitably made of, for example, cross linked polystyrene resin, polyethylene glycol- polystyrene resin, and any other substance which may be used as such and which would be known or obvious to one of ordinary skill in the art.
- the term 'substituted resin-bound Rink-chlo ⁇ de intermediate is used herein at all occurrences to mean the intermediate produced by coupling a resin-bound Rink-chlo ⁇ de linker with a suitable nucleophile (with displacement of the chloride of the Rink linker) such that to the nucleophile is linked to the resin through the Rink linker.
- additional synthetic chemistry is used herein at all occurrences to mean chemical reactions which are performed on the substituted resin-bound Rink- chlo ⁇ de intermediate prior to cleavage of the nucleophile from the polymeric resin, wherein said chemical reactions are compatible with and non-reactive with the Rink- chlo ⁇ de linker and may be used to prepare derivatives of the nucleophile It will be understood by the skilled artisan that the additional synthetic chemistry performed on the substituted resin-bound Rink-chlo ⁇ de intermediate, is done so prior to cleavage of the de ⁇ vatized nucleophile.
- reaction-bound synthesis and “solid phase synthesis” are used herein interchangeably to mean a series of chemical reactions used to prepare either a single molecule/compound or a library of molecularly diverse compounds, wherein the chemical reactions are performed on a compound which is bound to a polymer resin through a linkage, in particular, a Rink-chlo ⁇ de linkage
- the resin-bound Rmk-acid linker 1-Scheme 1 can be converted to the resin-bound Rink-chlo ⁇ de resin of this invention, 2-Scheme 1, by treatment of the resin-bound Rink- acid linker with t ⁇ phenyl phosphine and hexachloroethane 2-Scheme 1 so obtained is stable at room temperature for several days and can be used without any loss of activity
- Rink-chloride efficiently reacts with primary and secondary amines, anilines, alcohols, phenols, thiols, thiophenols, and carboxyhc acids.
- the coupling is usually carried out in dichloroethane in the presence of Hunig's base, under inert atmosphere for 18-26 hours at room temperature.
- the extent of coupling efficiency is monitored by MASNMR and then by cleaving the product from the resin with about 3-5% TFA in CHoCb- Release of the ligands from the resin is complete within 30 minutes as evidenced by MASNMR of the residual resin.
- Table I the coupling is general and highly efficient. While cleavage from the resin is facile, it is sufficiently stable enough to carry out a wide range of chemistry commonly used in small molecule library construction.
- another aspect of the invention is in a method for synthesizing a 5 compound by resin-bound synthesis comprising the steps of: (a) converting a resin- bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I)
- this invention is in a method for synthesizing a library of molecularly diverse compounds by resin-bound synthesis, comprising the steps of: (a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I)
- the libraries generated from either of the the synthetic methods are molecularly diverse and are prepared simultaneously.
- the libraries are prepared on the polymer resins using the Rink-chloride linker described herein.
- the compound to be derivatized (suitable nucleophile) is attached to the polymer resin through the Rink-chloride linker to give a substituted resin-bound Rink-chloride intermediate.
- the substituent(s) are modified by reacting the resin-bound Rink-chloride intermediate, with a mixture of reagents.
- aliquots of the resin-bound Rink-chloride intermediate are reacted with individual reagents each one of which will modify a position on the core of the resin-bound nucleophile, and then the resultant products are mixed together to form the library of derivatized resin-bound intermediates.
- This library may then be further derivatized by repeating the process of dividing and recombining the intermediates formed by the additional synthetic chemistry. It will be clear to one of ordinary skill in the art that when the libraries of the invention are prepared according to the instant disclosure, each polymer support bears a single species created by the additional synthetic chemistry performed on the substituted resin-bound Rink-chloride intermediate.
- the steps of optionally dividing and recombining the resin-bound aryl silane intermediate into portions are for purposes of varying the derivatization on the resin-bound nucleophiles which are generated by the combinatorial synthesis.
- the resin-bound nucleophile intermediates may be divided into portions at any point during the synthetic sequence. The portions may be recombined at any point during the sequence or, further iterations may be applied if more derivatization is required.
- the steps of dividing the portions, performing additional synthetic chemistry and recombining the portions may each be carried out more than once, depending upon the type of diversity required for the library of end-product compounds being prepared.
- the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectrometry or mass spectrometry. The compounds may be characterized while remaining resin-bound or they can be cleaved from the resin using the conditions described above, and then analyzed.
- a partial array of compound members of the library may be cleaved from the resin, characterized and analyzed, while leaving a partial array of the compound members of the library bound to the resin.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
Abstract
This invention relates to a novel linker for use in solid phase chemistry, its preparation and methods of use of the linker.
Description
RINK-CHLORIDE LINKER FOR SOLID PHASE ORGANIC SYNTHESIS OF ORGANIC MOLECULES
FIELD OF THE INVENTION This invention relates to a novel linker for use in solid phase chemistry, its preparation and methods of use of the linker.
BACKGROUND OF THE INVENTION
In the continuing search for new chemical moieties that can effectively modulate a variety of biological processes, the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks. The biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
In an effort to reduce the time and expense involved in screening a large number of randomly chosen compounds for biological activity, several developments have been made to provide libraries of compounds for the discovery of lead compounds. The chemical generation of molecular diversity has become a major tool in the search for novel lead structures. Currently, the knownjnethods for chemically generating large numbers of molecularly diverse compounds generally involve the use of solid phase synthesis, in particular to synthesize and identify peptides and peptide libraries. See, for example. Lebl et al., Int. J Pept. Prot Res . 41, p. 201 ( 1993) which discloses methodologies providing selectively cleavable linkers between peptide and resin such that a certain amount of peptide can be liberated from the resin and assayed in soluble form while some of the peptide still remains attached to the resin, where it can be sequenced; Lam et al., Nature. 354. p 82 ( 1991 ) and (WO 92/00091 ) which disclose a method of synthesis of linear peptides on a solid support such as polystyrene or polyacryiamide resin; Gevsen et al., J. Immunol. Meth , 102. p. 259 ( 1987) which discloses the synthesis of peptides on deπvatized polystyrene pins which are arranged on a block in such a way that they correspond to the arrangement of wells in a 96-well microtiter plate, and Houghten et al., Nature. 354, p 84 (1991) and WO 92/09300 which disclose an approach to de novo determination of antibody or receptor binding sequences involving soluble peptide pools.
The major drawback, aside from technical considerations, with all of these methods for lead generation is the quality of the lead. Linear peptides historically
have represented relatively poor leads for pharmaceutical design. In particular, there is no rational strategy for conversion of a linear peptide into a non-peptide lead. As noted above, one must resort to screening large databanks of compounds, with each compound being tested individually, in order to determine non-peptide leads for peptide receptors.
In this respect, there has been increasing interest in the application of solid phase synthesis to the preparation of organic compounds, especially in the context of combinatorial chemistry and multiple simultaneous synthesis, or parallel synthesis. One of the limitations in the solid phase approach in general, involves the linker by which the organic molecule is attached to the solid support. The Rink linker (Rink, H., Tetrahedron Lett., 1987,25, 3787-3790) has been effectively applied to the synthesis of some chemical libraries (Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924-928; Norman, T C, Gray, N. S.; Koh, J. T.; Schultz, P G. f Am Chem. Soc. 1996, p. 118. 7430-7431, Ward, Y. D.; Farina, V Tetrahedron Lett., 1996, 57, 6993-6996), because of the ease of use and mild conditions for release of the library component. However the Rink linker is currently limited to use in the preparation of amides and carboxy c acids. Therefore, a need exists for a Rink linker useful for a broader range of solid phase chemistry. Herein, we describe the preparation of a Rink-chloπde linker, which allows a very general and practical method for the attachment of, inter alia, amines, alcohols and thiols to a solid support.
SUMMARY OF THE INVENTION
This invention relates to a novel solid phase Rink linker of formula (I), hereinafter referred to as a resin-bound Rink-chloπde linker or a Rink-chloπde linker This represents a significant improvement over the current use of the Rink- acid linker. At present the use of the known Rink-acid linker is limited to preparing amides and carboxyhc acids. The use of the instant improved Rink-chloπde linker of formula (I) makes Rink technology available to a broad number of functional group attachments. The use of the Rink-chloπde linker allows a very general and practical method for the attachment of amines, alcohols and thiols, including phenols and thiophenols to a solid support. Therefore, another aspect of the instant invention is in a method for making compounds by resin-bound synthesis using the Rink- chloπde linker in solid phase synthesis. This method is applicable to making combinatorial libraries of compounds designed around a core molecular structure using known methods of solid phase combinatorial chemistry or multiple simultaneous synthesis ("parallel synthesis") The compounds or libraries of
compounds made using this linker may be tested in biologically assays designed to test for a particular physical characteristic potentially useful in drug therapy
DETAILED DESCRIPTION OF THE INVENTION The terms "resin." "solid support." "inert resin, ' polymeric resin" or
"polymeric resin support" are used herein at all occurrences to mean a bead or other solid support such as beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, grafted co-poly beads, polyacryiamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bιs-acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface. The solid support is suitably made of, for example, cross linked polystyrene resin, polyethylene glycol- polystyrene resin, and any other substance which may be used as such and which would be known or obvious to one of ordinary skill in the art. The term 'substituted resin-bound Rink-chloπde intermediate" is used herein at all occurrences to mean the intermediate produced by coupling a resin-bound Rink-chloπde linker with a suitable nucleophile (with displacement of the chloride of the Rink linker) such that to the nucleophile is linked to the resin through the Rink linker. The term "additional synthetic chemistry" is used herein at all occurrences to mean chemical reactions which are performed on the substituted resin-bound Rink- chloπde intermediate prior to cleavage of the nucleophile from the polymeric resin, wherein said chemical reactions are compatible with and non-reactive with the Rink- chloπde linker and may be used to prepare derivatives of the nucleophile It will be understood by the skilled artisan that the additional synthetic chemistry performed on the substituted resin-bound Rink-chloπde intermediate, is done so prior to cleavage of the deπvatized nucleophile. Chemical reactions which are incompatible with the nucleophile/Rink-chloπde linkage, i.e., they cause cleavage of the nucleophile from the Rink-chloπde linker, are not among the additional synthetic chemistry that may be used in the methods of this invention
The terms "resin-bound synthesis" and "solid phase synthesis" are used herein interchangeably to mean a series of chemical reactions used to prepare either a single molecule/compound or a library of molecularly diverse compounds, wherein the chemical reactions are performed on a compound which is bound to a polymer resin through a linkage, in particular, a Rink-chloπde linkage
Chemical synthesis on solid supports has become a cornerstone in the generation of small organic molecule combinatorial libraries Paramount to the success of any sohd-
phase synthetic strategy is a reliable and general method for coupling the initial starting materials onto the solid support, namely through linker technology Such linker technology should also be amenable to ready cleavage of the reaction products under relatively mild conditions, and without compromising the structure of the reaction products The Rink linker has been effectively applied to the synthesis of some chemical libraries because of its ease of use and the mild conditions for release of library components from the solid support However the Rink technology is currently limited to the preparation of amides and carboxyhc acids Herein, we describe the preparation and utility of a Rink-chloπde linker, which allows a very general and practical method for the attachment of amines, alcohols and thiols to a solid support, deπvatization of these resin- bound compounds, and their eventual release from the resin with tnfluoroacetic acid
The resin-bound Rmk-acid linker 1-Scheme 1 can be converted to the resin-bound Rink-chloπde resin of this invention, 2-Scheme 1, by treatment of the resin-bound Rink- acid linker with tπphenyl phosphine and hexachloroethane 2-Scheme 1 so obtained is stable at room temperature for several days and can be used without any loss of activity
Scheme 1
2-Scheme 1 can be reacted cleanly with a variety of nucleophiles ("Nu") under mild reaction conditions (see. Scheme 2 and Table I below) The nucleophiles depicted herein are either commercially available or can be made using known procedures
Scheme 2
Table I
Rink-chloride efficiently reacts with primary and secondary amines, anilines, alcohols, phenols, thiols, thiophenols, and carboxyhc acids. The coupling is usually carried out in dichloroethane in the presence of Hunig's base, under inert atmosphere for 18-26 hours at room temperature. The extent of coupling efficiency is monitored by MASNMR and then by cleaving the product from the resin with about 3-5% TFA in
CHoCb- Release of the ligands from the resin is complete within 30 minutes as evidenced by MASNMR of the residual resin. As is apparent from Table I, the coupling is general and highly efficient. While cleavage from the resin is facile, it is sufficiently stable enough to carry out a wide range of chemistry commonly used in small molecule library construction. Some illustrative examples are shown in Scheme 3.
Scheme 3
1. FMOC-glyine acid chloride/ Hunig's base
2. 20%pιperιdιne m DMF
0
It will be understood that after making the substituted resin-bound Rink- chloride intermediate, and prior to cleavage with TFA. additional syntheic chemistry may be performed on the intermediate in order to derivatize the nucleophile core. Therefore, another aspect of the invention is in a method for synthesizing a 5 compound by resin-bound synthesis comprising the steps of: (a) converting a resin- bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I)
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate; and (c) performing additional synthetic chemistry on the substituted resin-bound Rink- chloride intermediate to provide a resin-bound derivatized nucleophile. The resin-bound derivatized nucleophile can remain bound to the resin for storage and/or further derivatization, or it may be cleaved from the resin with between about 3 and 5% TFA.
In yet another aspect, this invention is in a method for synthesizing a library of molecularly diverse compounds by resin-bound synthesis, comprising the steps of: (a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I)
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate; (c) optionally dividing said substituted resin-bound Rink-chloride intermediate into a plurality of portions; (d) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile; and (e) optionally recombining the portions. Based upon the disclosure herein, it will be clear to one of ordinary skill in the art that there are many possible synthetic approaches to creating the libraries of this invention. For example the libraries may be prepared using the split and mix technique or parallel synthesis techniques. The libraries generated from either of the the synthetic methods are molecularly diverse and are prepared simultaneously. The libraries are prepared on the polymer resins using the Rink-chloride linker described herein. For example, the compound to be derivatized (suitable nucleophile), is
attached to the polymer resin through the Rink-chloride linker to give a substituted resin-bound Rink-chloride intermediate. In one embodiment, the substituent(s) are modified by reacting the resin-bound Rink-chloride intermediate, with a mixture of reagents. In an alternative embodiment, aliquots of the resin-bound Rink-chloride intermediate are reacted with individual reagents each one of which will modify a position on the core of the resin-bound nucleophile, and then the resultant products are mixed together to form the library of derivatized resin-bound intermediates. This library may then be further derivatized by repeating the process of dividing and recombining the intermediates formed by the additional synthetic chemistry. It will be clear to one of ordinary skill in the art that when the libraries of the invention are prepared according to the instant disclosure, each polymer support bears a single species created by the additional synthetic chemistry performed on the substituted resin-bound Rink-chloride intermediate.
It will be obvious to one of skill in the art that the steps of optionally dividing and recombining the resin-bound aryl silane intermediate into portions are for purposes of varying the derivatization on the resin-bound nucleophiles which are generated by the combinatorial synthesis. Of course, it will be obvious to the skilled artisan that the resin-bound nucleophile intermediates may be divided into portions at any point during the synthetic sequence. The portions may be recombined at any point during the sequence or, further iterations may be applied if more derivatization is required. Therefore, it will be obvious to the skilled artisan that the steps of dividing the portions, performing additional synthetic chemistry and recombining the portions, may each be carried out more than once, depending upon the type of diversity required for the library of end-product compounds being prepared. According to this invention, after the additional synthetic chemistry has been performed on the resin-bound aryl silane intermediate so that a library of molecularly diverse compounds has been prepared, the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectrometry or mass spectrometry. The compounds may be characterized while remaining resin-bound or they can be cleaved from the resin using the conditions described above, and then analyzed. In addition, a partial array of compound members of the library may be cleaved from the resin, characterized and analyzed, while leaving a partial array of the compound members of the library bound to the resin.
EXAMPLES Preparation of Rink-chloride (2-Scheme 1)
To a suspension of resin-bound Rink-acid, 1-Scheme 1, (l.Og, l.όmmol.) in THF (25mL) was added triphenylphosphine (2.32g, 8.8mmol.) and hexachloroethane (2.13g, 8.8mmol.). The reaction mixture was agitated with a constant flow of argon for 6h. The resin-bound Rink-chloride, 2-Scheme 1, was filtered and washed with THF and acetone. Completion of the reaction was affirmed by chlorine analysis and MASNMR (the signal for CH(OH)at δ 5.85 disappears completly). Chlorine analysis indicated a stoichometric amount of chlorine.
Reaction of rink-chloride with various nucleophiles
To a suspension of 2-Scheme 1 (0.96g, l.όmMol.) in dichloroethane (25mL) was added Hunig's base (lmL) and the requisite nucleophile (lOmMol.). The reaction mixture was agitated with a constant flow of argon for 6-12h. The resin was filtered and washed with dichloromethane, MeOH, H2O, EtOH, CH2CI2 and MeOH.
Completion of the reaction was confirmed by MASNMR, IR or elemental analysis. Elemental analysis indicates no chlorine and a stoichometric amount of nitrogen or sulfur for the appropriate compounds.
Cleavage from Rink-linked ligands
3% TFA/CH2CI2 was added to the substituted resin-bound Rink chloride moieties, either as individual beads or in bulk quantity. The cleavage was carried out for 30 min., and the product was isolated by extraction with 1: 1/ MeOH:MeCN. All the cleaved products from Table I were identified by comparing them with an authentic sample of the starting material (nucleophile).
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows.
Claims
1. A resin-bound compound of formula (I)
2. The resin-bound compound of formula (I) as claimed in claim 1 , made by a method comprising reacting a resin-bound Rink-acid linker with triphenyl phosphine and hexachloroethane.
3. A method for synthesizing a compound by resin-bound synthesis comprising the steps of:
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink- chloride linker of formula (I)
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate; and
(c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile.
4. The method as claimed in claim 3, further comprising the step of cleaving the derivatized nucleophile from the substituted resin-bound Rink-chloride intermediate.
5. A method for synthesizing a compound by resin-bound synthesis comprising the steps of:
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink- chloride linker of formula (I)
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
(c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile; and
(d) cleaving the resin-bound derivatized nucleophile.
6. A method for preparing a library of diverse compounds by resin- bound synthesis, comprising the steps of:
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink- chloride linker of formula (I)
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
(c) optionally dividing said substituted resin-bound Rink-chloride intermediate into a plurality of portions;
(d) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile; and (e) optionally recombining the portions.
7. The method of claim 6 wherein the steps of (c) dividing the portions, (d) performing additional synthetic chemistry, and (e) recombining the portions, are carried out more than once.
8. The method of claim 5 wherein the derivatized nucleophile is cleaved from the resin-bound Rink-chloride intermediate by reaction with between about 3 to 5% TFA.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4469697P | 1997-03-28 | 1997-03-28 | |
| PCT/US1998/005860 WO1998044329A2 (en) | 1997-03-28 | 1998-03-26 | Rink-chloride linker for solid phase organic synthesis of organic molecules |
| US44696P | 2008-04-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0971947A2 true EP0971947A2 (en) | 2000-01-19 |
| EP0971947A4 EP0971947A4 (en) | 2005-01-26 |
Family
ID=21933821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98913115A Withdrawn EP0971947A4 (en) | 1997-03-28 | 1998-03-26 | Rink-chloride linker for solid phase organic synthesis of organic molecules |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0971947A4 (en) |
| JP (1) | JP2001518946A (en) |
| CA (1) | CA2285175A1 (en) |
| WO (1) | WO1998044329A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL156677A0 (en) | 2001-01-12 | 2004-01-04 | Amersham Plc | Perfluoro sulfonyl halides and related species as polymer support modifiers |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69130333T2 (en) * | 1990-08-31 | 1999-03-04 | Regents Of The University Of Minnesota, Minneapolis, Minn. | Resins for solid peptide synthesis |
| US5268423A (en) * | 1992-02-28 | 1993-12-07 | New York University | Method for preparation of peptide synthesis resins and peptide synthesis resins |
| JPH05271332A (en) * | 1992-03-30 | 1993-10-19 | Nippon Steel Chem Co Ltd | Production of amino group-bearing styrene-based polymer |
| WO1994002515A1 (en) * | 1992-07-21 | 1994-02-03 | Bunsen Rush Laboratories Inc. | Oligomer library formats and methods relating thereto |
| GB9502225D0 (en) * | 1995-02-04 | 1995-03-22 | Zeneca Ltd | Method |
| US5684130A (en) * | 1995-06-05 | 1997-11-04 | Solid Phase Sciences Corporation | Process for synthesis of organic compounds using magnetic particles |
-
1998
- 1998-03-26 CA CA002285175A patent/CA2285175A1/en not_active Abandoned
- 1998-03-26 JP JP54176998A patent/JP2001518946A/en active Pending
- 1998-03-26 WO PCT/US1998/005860 patent/WO1998044329A2/en not_active Ceased
- 1998-03-26 EP EP98913115A patent/EP0971947A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0971947A4 (en) | 2005-01-26 |
| CA2285175A1 (en) | 1998-10-08 |
| JP2001518946A (en) | 2001-10-16 |
| WO1998044329A3 (en) | 1998-12-03 |
| WO1998044329A2 (en) | 1998-10-08 |
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