WO2000078740A1 - Amorceurs a support solide et polymeres fonctionnels utilises en synthese organique et chimie combinatoire - Google Patents

Amorceurs a support solide et polymeres fonctionnels utilises en synthese organique et chimie combinatoire Download PDF

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WO2000078740A1
WO2000078740A1 PCT/US2000/017038 US0017038W WO0078740A1 WO 2000078740 A1 WO2000078740 A1 WO 2000078740A1 US 0017038 W US0017038 W US 0017038W WO 0078740 A1 WO0078740 A1 WO 0078740A1
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poly
divinylbenzene
styrene
compound according
content
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PCT/US2000/017038
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English (en)
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Lalgudi Sankaran Harikrishnan
John Cooke Hodges
Craig William Lindsley
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Warner-Lambert Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F4/00—Polymerisation catalysts
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to novel solid-supported initiators and solid-supported functional polymers, to processes for their preparation and to their use in organic synthesis and combinatorial chemistry.
  • Organic synthesis has proven to be a highly effective means for preparation of molecules with useful biological activities which may be employed in the treatment of human, animal, and plant diseases.
  • Combinatorial chemistry is a means of performing many organic syntheses concurrently or in parallel arrays, thereby increasing the rate at which compounds may be synthesized.
  • a multi-step organic synthesis is usually required. Each step consists of reacting various chemicals to produce a product which is normally purified before continuing with the next step. Purification is typically the most time consuming part of organic synthesis. The time spent on purification is especially critical in combinatorial chemistry since hundreds or even thousands of reactions are often carried out in parallel. Thus, methods which enable simple, rapid, and readily automated purification are of value to the practice of both organic synthesis and combinatorial chemistry.
  • Solid-supported reagents which cause a chemical transformation of a compound in solution provide a convenient and rapid means of purification since they can be removed from the desired product by filtration.
  • Solid-supported reagents are typically prepared by chemical reactions that attach individual molecules of the desired reagent to a pre-formed solid support either by covalent bonding or ionic interaction.
  • Solid-supported scavenging reagents also provide a convenient and rapid means of purification since they selectively react with certain components of a mixture in solution, thereby removing them from solution to the solid phase where they can be easily separated from the unbound components by filtration.
  • a solid- supported scavenger may be used in one of two ways.
  • the scavenger resin can also be designed to selectively react with the desired product. With the product sequestered on the resin, any contaminants may be rinsed away. The product is then chemically cleaved from the resin in a purified form. This latter use of a scavenging resin is often referred to as "catch and release.” Solid-supported scavenging reagents are typically prepared by chemical reactions, which result in the covalent attachment of individual molecules of the scavenger reagent to a pre-formed solid support.
  • Solid-phase synthesis provides yet another means of facile purification.
  • a solid support is covalently linked to the starting material of a synthesis.
  • the reactions of the synthesis are carried out stepwise with excess reagents. After each reaction, the unreacted reagents and byproducts are rinsed from the solid-supported product. At the end of the synthesis, the product is chemically cleaved from the solid-support in a substantially pure form.
  • Solid phase synthesis resins are typically prepared by chemical reactions which result in the covalent attachment of linker functionalities to a pre-formed solid support. Alternatively, they may be prepared by aqueous suspension co-polymerization of unfunctionalized monomers and monomers bearing the linker functionality.
  • a suspension polymerization is typically carried out by vigorously stirring and heating one or more monomers and an initiator in water.
  • the monomers and the initiator being insoluble in water, form droplets. As they polymerize, the droplets form solid resin beads which are of sufficient molecular weight to be insoluble in organic solvents.
  • Aqueous suspension polymerization requires that any functionality on the monomers not be reactive with water nor promote dissolution of the monomer in water. This limits the range of monomers that may be utilized.
  • a disadvantage with some solid-supported reagents and solid-supported scavengers is their low loading of reactive groups per gram of solid support.
  • an isocyanate scavenger resin with 1.1 mMol of isocyanate groups per gram of resin has recently been described (Booth R.J. and Hodges J.C., Polymer- Supported Quenching Reagents for Parallel Purification, J. Am. Chem. Soc. , 1997;119:4882-4886).
  • An isocyanate resin with double or triple this loading would be very useful, since less scavenger resin would need to be added in order to affect the same degree of purification.
  • TEMPO 2,2,6,6-tetramethylpiperidine-N-oxyl
  • OH-TEMPO 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl
  • 2,2,6,6-tetramethylpiperidine-l-oxyl oxo-TEMPO
  • O-alkyl derivatives such as l-Phenyl-l-(2',2',6',6'-tetramethyl- -piperidinyloxy)-ethane (1-Phenylethyl-TEMPO)
  • oxo-TEMPO 2,2,6,6-tetramethylpiperidine-l-oxyl
  • O-alkyl derivatives such as l-Phenyl-l-(2',2',6',6'-tetramethyl- -piperidinyloxy)-ethane (1-Phenylethyl-TEMPO
  • Heating 1-Phenylethyl-TEMPO above 123°C causes it to reversibly fragment into a
  • TEMPO radical and a phenylethyl radical initiates polymerization of the styrene.
  • the resulting polystyrene has a low degree of polydispersity. In other words, the polymer chain length is highly homogeneous and related to the stoichiometry of the starting reaction mixture.
  • Each molecule of 1-Phenylethyl-TEMPO grows one polymer chain of approximately 10 monomer units, the terminus of which is capped with a TEMPO residue. Subsequently, it is possible to use the first polymer as an initiator for an even larger polymer as shown by the second vertical arrow of Scheme 1.
  • Heating of the first polymer with excess 4-bromostyrene causes continued polymerization to give a polymer of approximately twice the number of monomer units in two blocks, one of which is polystyrene and the other of which is poly (4-bromostyrene).
  • the term "living free-radical polymerization” arises from the potential ability to start, stop, and continue polymerization reactions in repeated cycles. The polymerization reaction "lives” a long time since chain termination reactions that would “kill” the polymerization reaction are inhibited by the presence of the TEMPO radical.
  • Scheme 2 shows an alternate method by which nitroxide initiators may be used to create block co-polymers. Soluble poly(styrene-chloromethylstyrene) is reacted with 2-hydroxy-l-phenylethyl-TEMPO in the presence of a strong base.
  • nitroxide functionalized polymer wherein an ether linkage connects 1-Phenethyl-TEMPO to the soluble polystyrene.
  • This nitroxide functionalized polymer is heated with a mixture of styrene and chloromethylstyrene to form a branched polymer product wherein chains of poly(styrene-chloromethylstyrene) emanate from the phenyl groups of the core polystyrene.
  • US Patent 5,767,238 titled “Inverse Solid Phase Synthesis” discloses: "A method of inverse solid phase synthesis comprising the steps of: (a) reacting at least two reactants in a solution to obtain a product; and (b) removing at least one unreacted said reactants with a solid phase matrix wherein said solid phase matrix covalently binds said at least one unreacted said reactants, leaving substantially all of said product in said solution.”
  • This patent is pertinent to the concept of solid- supported scavenging that is described above.
  • insoluble solid supports may be chemically modified to contain multiple cyclic nitroxide sites which can act as initiators to radical polymerization.
  • solid-supported functional polymers may be prepared from these solid-supported initiators.
  • a first aspect of the present invention is a compound of Formula I,
  • f ⁇ is an insoluble solid support selected from the group consisting of: poly(styrene-divinylbenzene), macroreticular poly(styrene-divinylbenzene), polystyrene which is radiation grafted to polypropylene, polystyrene which is radiation grafted to polyethylene, polystyrene which is radiation grafted to poly(tetrafluoroethylene), and polystyrene which is radiation grafted to poly(ethylene-tetrafluoroethylene) wherein the insoluble solid support is in a shape selected from a bead, a tube, a rod, a ring, a disk, or a well; L is -CH 2 - -C(CH 3 ) 2 - -CH(CH 3 )-, -(CH 2 ) n CH(CN)-, -(CH 2 )nCH(CO 2 Me)-, -(CH 2 ) n CH(Ph)-,
  • n is zero or an integer from 1 to 5;
  • R1 , R2, and R- are each independently the same or different and are
  • n is zero or an integer from 1 to 5;
  • Y is H, Cl, Br, F, OH, or OMe
  • Z is s NCO, CO 2 Me, CO 2 Et, CO 2 (/-Pr), CO 2 ( ⁇ -BU), CO 2 (t-Bu), CN, CO 2 H,
  • COCl CO2CH(CF 3 )2, CO2(pentafluorophenyl), CO 2 (pentachlorophenyl), CO Ph, CO 2 (N-succinimidyl), C(OMe) 3 , C(OEt) 3 , CON(OCH 3 )CH 3 , CHO, CH 2 OH, or C(CH 3 ) 2 OH; and
  • a second aspect of the present invention is a process for preparing a compound of Formula I, as described above, which comprises conversion of a solid support to a compound of Formula I in one to eight synthetic steps, rinsing thoroughly with one or more solvents after each synthetic step.
  • a third aspect of the present invention is the use a compound of Formula I, as described above, in solution phase organic synthesis, solid-phase organic synthesis, and combinatorial chemistry, including its use as an initiator of solid-supported free-radical polymerization, its use as a solid-supported scavenger for purification of crude solution phase reaction mixtures, its use as a stationary phase for solid-phase organic synthesis, and its use as solid-supported reagents in solution phase organic synthesis.
  • Crude reaction product The result of a chemical reaction before any purification. This term is synonymous with crude product and crude reaction mixture.
  • Enhancing purity A For a single desired compound: The process of removing excess or unreacted starting reagents to the limit of detection by TLC or by NMR spectroscopy and/or reducing the content of any single byproduct to less than two mole percent, exclusive of solvents.
  • Solid support A material which does not dissolve in organic and/or aqueous solvents and mixtures thereof.
  • Insoluble polymer A polymeric compound which by virtue of its structure and high molecular weight is incapable of dissolving in organic and/or aqueous solvents and mixtures thereof.
  • Solid-supported scavenger A molecule which is attached to a an insoluble solid and binds to a starting reagent and/or to a byproduct in a covalent and/or ionic manner, thereby removing it from a solution.
  • a synonym for a polymer-supported quench reagent Table 1. Definitions and Abbreviations (cont'd)
  • Resin swelling solvent A solvent which penetrates pores of an insoluble polymer and causes it to increase in volume.
  • Soluble polymer A polymeric compound which by virtue of its structure and molecular weight is able to dissolve in selected solvents.
  • Radiation grafting The process for preparing a complex polymeric compound which entails treating a mixture of base polymer such as, for example, polyethylene, polypropylene, poly(ethylene-tetrafluoroethylene) or poly(tetrafluoroethylene), and a monomer such as, for example, styrene with ionizing radiation. This process results in the polymerization of polystyrene onto the base polymer.
  • base polymer such as, for example, polyethylene, polypropylene, poly(ethylene-tetrafluoroethylene) or poly(tetrafluoroethylene
  • a monomer such as, for example, styrene
  • Grafted copolymer A complex polymer that is produced by radiation grafting. A synonym for a radiation grafted copolymer.
  • Solid-supported polymer A polymeric compound which is covalently attached to an insoluble solid.
  • Functional polymer A polymer which bears multiple instances of chemically reactive functional groups.
  • Macroreticular A property of insoluble polymers indicating a rigid, highly crosslinked polymer which does not swell in any solvent and is porous.
  • H-DIPS- -ST (4-vinyl)phenyl-diisopropyl-silane
  • An insoluble solid support selected from the group consisting of: poly(styrene-divinylbenzene), macroreticular poly(styrene-divinylbenzene), polystyrene which is radiation grafted to polypropylene, polystyrene which is radiation grafted to polyethylene, polystyrene which is radiation grafted to poly(tetrafluoroethylene), and polystyrene which is radiation grafted to poly(ethylene-tetrafluoroethylene) wherein the insoluble solid support is in a shape selected from a bead, a tube, a rod, a ring, a disk, or a well
  • a preferred compound of Formula I is one, wherein ffj is an insoluble solid support selected from the group consisting of: poly(styrene-divinylbenzene) and macroreticular poly(styrene- divinylbenzene) in the shape of a bead.
  • Formula I is one wherein fjj is an insoluble solid support selected from the group consisting of: polystyrene which is radiation grafted to polypropylene, polystyrene which is radiation grafted to polyethylene, polystyrene which is radiation grafted to poly(tetrafluoroethylene) and polystyrene which is radiation grafted to poly(ethylene-tetrafluoroethylene) in the shape selected from a tube, a rod, a ring, a disk, or a well.
  • another more preferred compound of Formula I is one wherein L is -CH 2 - -(CH2) n C(CH , Ph)-, or
  • another more preferred compound of Formula I is one wherein m and q are equal to zero.
  • another more preferred compound of Formula I is one wherein m is equal to zero, and q is an integer from 1 to 300.
  • another more preferred compound of Formula I is one wherein m is an integer from 1 to 100, and q is an integer from 1 to 300.
  • another more preferred compound of Formula I is one wherein X is NCO, CH 2 NCO, CH(CH 3 )NCO or C(CH 3 ) 2 NCO, and Y is H.
  • another more preferred compound of Formula I is one wherein X is (CH 2 ) n NH 2 , (CH ) n N(Me)2, (CH 2 ) n N(Et) 2 , (CH 2 ) n (iPr)2, CH(CH 3 )NH 2 , C(CH 3 ) 2 NH 2 , CH 2 NHCH2CH 2 NH2,
  • another more preferred compound of Formula I is one wherein X is (CH 2 ) n SH, CH2NHCH 2 CH 2 SH, or
  • another more preferred compound of Formula I is one wherein X is (CH 2 ) n Cl, (CH 2 ) n Br, (CH ) n I, (CH 2 ) n OH, or
  • another more preferred compound of Formula I is one wherein X is CO 2 Me, CO 2 Et, CO2(t-Bu), CO H, COCl, CO2CH(CF 3 )2, CO2Ph, C ⁇ 2(pentafluorophenyl), CO2(pentachlorophenyl),
  • a most preferred compound of Formula I is one wherein Z is NCO, CO2Me, CO2Et, CO ( ⁇ ' -Pr), CO 2 (n-Bu),
  • another most preferred compound of Formula I is one wherein wherein X is (CH ) n Si(Me) 2 H, (CH 2 ) n Si(Et) 2 H, (CH 2 ) n Si(iPr) 2 H, (CH 2 ) n Si(Me) 2 Cl, (CH 2 ) n Si(Et) 2 Cl or (CH 2 ) n Si(iPr) 2 Cl.
  • another most preferred compound of Formula I is one wherein R+ is CH2 and R ⁇ is CH 3 .
  • Particularly valuable in the first aspect of the present invention is a compound selected from the group consisting of:
  • fjgjp is a poly(styrene-divinylbenzene) resin with 1 % to 2% divinylbenzene content, and the nitrogen content is 0.1 to 4 mMol per gram;
  • Ijj is a poly(styrene-divinylbenzene) resin with 1 % to 2% divinylbenzene content, and the nitrogen content is 0.1 to 4 mMol per gram;
  • 1 JP is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content, and the nitrogen content is 0.1 to 4 mMol per gram;
  • IjjjP is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content, q is from 1 to 50 with an average of between 5 and 30 and the isocyanate content is 1 to 4 mMol per gram;
  • Ij is a poly(styrene-divinylbenzene) resin with 1 % to 2% divinylbenzene content, q is from 1 to 50 with an average of between 5 and 30 and the isocyanate content is 1 to 4 mMol per gram;
  • P is a poly(styrene-divinylbenzene) resin with 1 % to 2% divinylbenzene content, q is from 1 to 50 with an average of between 5 and 30, and the chlorine content is 1 to 4 mMol per gram;
  • P is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content, q is from 1 to 50 with an average of between 5 and 30, and the alkene content is 1 to 4 mMol per gram;
  • jP is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content, q is from 1 to 50 with an average of between 5 and 30, and the hydroxyl content is 1 to 4 mMol per gram;
  • H is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content, q is from 1 to 50 with an average of between 5 and 30, and the bromine content is 1 to 4 mMol per gram;
  • UP is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content
  • q is from 1 to 80 with an average of between 10 and 60
  • bromine content is 1 to 6 mMol per gram
  • I is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content, q is from 1 to 80 with an average of between 10 and 60, and the isocyanate content is 1 to 6 mMol per gram;
  • ijj is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content
  • q is from 1 to 50 with an average of between 5 and 30, and the isocyanate content is 1 to 6 mMol per gram.
  • WW is a poly(styrene-divinylbenzene) resin with 1% to 2% divinylbenzene content
  • q is from 1 to 100 with an average between 10 and 60
  • Si content is 1 to 6 mMol per gram.
  • a compound of Formula I wherein fjjP, L, Rl, m, R ⁇ , w, R ⁇ , p, q, R4, R5 ? and b are as defined above can be prepared by the general procedures, as set forth in Schemes 3-6. These schemes provide typical procedures for preparing compounds of Formula I. All structures in Schemes 3-6 which are numbered by bold arabic numerals represent a compound of Formula I.
  • a process for the preparation of a compound of Formula I may be one or two chemical transformations from known or commercially available solid supports.
  • the chemical modification of an insoluble support to covalently attach multiple cyclic nitroxide substituents to the solid support gives a compound of Formula I wherein m and q are zero.
  • Scheme 3 shows two representative illustrations. Reaction of the sodium salt of TEMPO with Merrifield resin in DMF gives 1. Heating of 1 in the presence of MeST gives 2. Both 1 and 2 are useful as solid-supported initiators of free radical polymerization.
  • Scheme 5 shows the preparation of 11, 14, 15, 16, and 17 which are useful as solid-supported initiators of free radical polymerization.
  • Schemes 3, 4, and 10 Additional processes for preparing a compound of Formula 1 are shown in Schemes 3, 4, and 10.
  • This process comprises: (1) chemical modification of an insoluble support to covalently attach multiple cyclic nitroxide substituents to the solid support, (2) heating the nitroxide-modified solid support with one or more substituted styrene and/or acrylate monomers to grow polymeric chains onto the solid support, (3) rinsing of the solid-supported polymer to remove excess monomer(s) and unattached polymer(s), and (4) chemical transformation of functional groups on the polymer as necessary to create a compound of Formula 1 wherein m is zero and q is an integer from 1 to 300.
  • Heating the solid-supported initiator, 1 with an acrylate monomer affords the solid-supported polymer 3 and heating 1 with a styrene monomer affords 4 (Scheme 3).
  • the point of attachment of the cyclic nitroxide in the solid-supported initiator is a primary carbon, as is the case for 1
  • the polymerization reaction results in solid-supported polymers which have a high degree polydispersity. That is to say that individual polymer chains of 3 and 4 vary in length from the point at which they are linked to the solid support.
  • heating 2 with an acrylate monomer affords 5 and heating 2 with a styrene monomer affords 6.
  • the polymerization reaction results in solid-supported polymers which have a high degree of monodispersity.
  • the individual polymer chains of 5 and 6 are similar in length from the point at which they are linked to the solid support.
  • heating solid-supported initiators with a mixture of monomers as shown in Scheme 4 also provides a compound of Formula I.
  • An additional process for preparing a compound of Formula I comprises: (1) chemical modification of an insoluble support to covalently attach multiple cyclic nitroxide substituents to the solid support, (2) heating the nitroxide-modified solid support with a substituted styrene or acrylate monomer to grow polymeric chains onto the solid support, (3) rinsing of the solid-supported polymer to remove excess monomer and unattached polymer, (4) heating the resulting solid-supported polymer which still contains cyclic nitroxide moieties with one or more substituted styrene and/or acrylate monomers to extend the polymeric chains, (5) rinsing of the solid-supported polymer to remove excess monomers and unattached polymers, and (6) chemical transformation of functional groups on the polymer as necessary to create a compound of Formula 1 wherein m is an integer from 1 to 100 and q is an integer from 1 to 300.
  • the inhibitor may be destroyed in situ by addition of at least one molar equivalent of an isocyanate such as, for example, BuNCO, PhNCO and the like per equivalent of inhibitor.
  • the isocyanate reacts with the inhibitor.
  • the resulting inhibitor-isocyanate adducts have no effect on the polymerization process and are easily rinsed away from the desired solid-supported polymers.
  • an ⁇ -methylstyrene monomer along with either an acrylate monomer or a styrene monomer allows efficient synthesis of solid-supported polymers wherein the two monomers tend to alternate, i.e., a compound of Formula I wherein w and p are approximately one is produced. Alternation of the monomers within the solid-supported polymer chains is typically enhanced when the ⁇ -methylstyrene monomer composes at least 60 mole percent of the reaction mixture. In cases where both monomers have functionality, this provides a means of alternating two different types of functionality in solid-supported polymers.
  • the third aspect of the present invention is the use of a compound of Formula I, as described above, in solution phase, solid phase organic synthesis or combinatorial chemistry, including use as initiators of solid-supported free-radical polymerization, use as solid-supported scavengers for purification of crude solution phase reaction mixtures, use as a stationary phase for solid phase organic synthesis, and use as solid-supported reagents in solution phase organic synthesis.
  • Representative descriptions of the use of a compound of Formula I as solid- supported initiators of free radical polymerization are described above and shown in Schemes 3-6.
  • Representative descriptions of the use of a compound of Formula I as solid-supported scavengers, solid-supported reagents, and solid supports for solid phase synthesis are provided in Schemes 7-10. These schemes provide typical examples. All structures in Schemes 3-10 which are numbered by bold arabic numerals are examples of a compound of Formula I.
  • Scheme 7 shows the solid-supported scavenging of excess amine by 21 or 22 which are examples of a compound of Formula I with a high loading of isocyanate groups.
  • Scheme 8 shows the conversion of 2-(4-bromophenyl)-ethylamine to N- (2-(4-bromophenyl)ethyl)urea by treatment with 21, followed by treatment with TFA.
  • Scheme 9 shows a four-step solid phase synthesis of the urea derivative of biphenylalanine, ethyl ester using 22 as the solid support.
  • Scheme 10 shows post polymerization functionality transformations of 23 which lead to 24, 25, 26 and 27 and describes their utilities as solid-supported scavengers and solid supports for solid phase synthesis.
  • Scheme 11 shows a four-step solid phase synthesis of a chiral amide using 28 as the solid support.
  • EXAMPLE 2 (3-Phenyl-3-TEMPO-butvn-polv(ST-DVB resin (A compound of Formula I wherein L is CH 2 , m is equal to one, q is equal to zero,
  • R 1 is -CH 2 C(CH 3 )(Ph)-, R 4 is TEMPO)
  • the resin from Example 1 200 mg, 0.2 mmol N) and MeST (2 mL) are placed in a septum-capped tube.
  • the air in the tube is then purged by pressurizing and venting the tube with nitrogen or argon gas 20 times.
  • the septum-capped tube is then placed in an aluminum block which has been pre-heated to 130°C. Gentle mixing is optionally carried out by orbital shaking. After 12 hours, the tube is cooled to room temperature.
  • the resulting solid beads are collected by filtration and rinsed alternately with dichloromethane and methanol (five cycles of each solvent).
  • the air in the tube is then purged by pressurizing and venting the tube with nitrogen or argon gas 20 times.
  • the septum-capped tube is then placed in an aluminum block which has been pre-heated to 130°C. Gentle mixing is optionally carried out by orbital shaking. After 3 hours, the resulting polymeric mass is cooled to room temperature and treated with dichloromethane (6 mL). The mixture is shaken for about an hour until all of the soluble polymer dissolves. The insoluble beads are collected by filtration and rinsed alternately with dichloromethane and methanol (five cycles of each solvent).
  • the insoluble beads are dried in a reduced pressure oven at 45 °C for 6 hours to afford 470 mg of solid-supported poly(4-bromostyrene). Calc'd: Br, 39.14%. Found: Br, 38.88%.
  • the solid-supported poly(4-bromostyrene) produced contains
  • Method 2 (A compound of Formula I wherein L is CH 2 , m and o are one, p is zero, q is an integer from 10 to 60, R 1 is -CH C(CH3, Ph)-, R 2 is -CH 2 CH(4-bromophenyl)- R 4 is CH 2 , and all instances of R 5 are CH3)
  • the resin from Example 2 is used in place of the resin from Example 1 in
  • R 4 is TEMPO
  • the resin from Example 1 200 mg, 0.2 mMol) and TMI (2 mL, 10.1 mmol) are placed in a septum-capped tube.
  • the air in the tube is then purged by pressurizing and venting the tube with nitrogen or argon gas 20 times.
  • the septum- capped tube is then placed in an aluminum block which has been pre-heated to 130° C. Gentle mixing is optionally carried out by orbital shaking. After 18 hours the tube is cooled to room temperature.
  • the beads are then collected by filtration and washed with alternating portions of DCM and hexanes (five times each).
  • the beads are dried under suction on the filter, then transferred to a vial, and further dried in a reduced pressure oven at 45 °C overnight to afford 247 mg. Calc'd: N, 1.67%. Found: N, 1.62%.
  • Method 1 (A compound of Formula I wherein L is CH 2 , m is zero, w and p are one,
  • q is an integer from 1 to 50, R 2 is R3 is
  • R 4 is TEMPO ; and b is 1.0 ⁇ 0.3 mMol of poly (TMI-BA) per gram of insoluble solid support.)
  • Method 2 (A compound of Formula I wherein L is CH 2 , m is zero, w and p are one,
  • q is an integer from 5 to 30, R 2 is R3 is
  • R 4 is CH 2
  • all instances of R 5 are CH 3
  • b is 1.0 +
  • the resin from Example 4 50 mg, 0.8 mMol N/g
  • a mixture of TMI (0.7 mL, 3.5 mmol) plus BA (0.3 mL, 2.1 mMol) are placed in a septum-capped tube.
  • the air in the tube is then purged by pressurizing and venting the tube with nitrogen or argon gas 20 times.
  • the septum-capped tube is then placed in an aluminum block which has been pre-heated to 130°C. Gentle mixing is optionally carried out by orbital shaking. After 20 hours the tube was cooled to room temperature.
  • the resulting thick slurry was treated with DCM (5 mL) and shaken for about 10 minutes to disperse the beads.
  • the beads are then collected by filtration and washed with alternating portions of DCM and hexanes (five times each). After an additional wash with hexanes, the beads are dried under suction on the filter, then transferred to a vial, and further dried in a reduced pressure oven at 45 °C overnight. The yield is 295 mg. Calc'd: N, 3.91%. Found: N, 3.96%, indicating approximately
  • Solid-supported PolvG-Br-ST (A compound of Formula I wherein L is CH 2 , m and p are zero, w is one, q is an integer from 1 to 100, R 2 is -CH 2 CH(3-bromophenyl)-, R 4 is TEMPO, and b is 0.5 ⁇ 0.28 mMol of poly (3-Br-ST) per gram of insoluble solid support.)
  • Method 1 (No solvent)
  • 3-Br-ST is distilled on a Kugelrohr apparatus ( ⁇ 1 mmHg, 75-80°C) immediately prior to use.
  • a mixture of resin prepared by the method of Example 1 (0.5 mMol N/g, 100 mg, 50 ⁇ Mol) and 3-Br-ST (0.5 g, 2.73 mMol) is flushed with argon and heated as in Example 3, Method 1.
  • the cooled polymeric mass is treated with DCM (5 mL) and shaken for 90 minutes. The tube was then allowed to stand for 15 minutes. A small quantity of beads float whereas the rest sink.
  • a Pasteur pipet is used to transfer the beads that sink to a filter, adding DCM as necessary to complete the transfer.
  • a mixture of resin prepared by the method of Example 1 (0.5 mMol N/g, 200 mg, 100 ⁇ Mol) and C1CH 2 -ST (a mixture of 3 and 4 isomers, 2.0 mL) is flushed with argon and heated as in Example 3, Method 1.
  • the cooled polymeric mass is refluxed in chloroform (20 mL).
  • the portion of the beads that is easily freed from the mass is collected by filtration and washed with alternating portions of
  • EXAMPLE 8 Solid-supported PolvfflOCH -ST (A compound of Formula I wherein L is CH 2 , m and p are equal to zero, w is one, q is an integer from 1 to 100, R 2 is -CH 2 CH(4-(hydroxymethyl)phenyl)-, R 4 is TEMPO, and b is 0.63 ⁇ 0.28 mMol of poly (HOCH -ST) per gram of insoluble solid support.)
  • a mixture of resin prepared by the method of Example 1 (0.63 mMol N/g, 150 mg, 90 ⁇ Mol) and HOCH 2 -ST (a mixture of 3 and 4 isomers, 0.8 mL) is flushed with argon and heated as in Example 3, Method 1.
  • the cooled polymeric mass is shaken with DCM (6 mL) for 1 hour and filtered.
  • the resin beads are washed with alternating portions of MeOH and DCM (five times each). After a final wash with MeOH, the beads are dried in a reduced pressure oven to afford 275 mg of solid-supported poly(HOCH 2 -ST).
  • Solid-supported Poly(BA) (A compound of Formula I wherein L is CH 2 , m and p are zero, w is one, q is an integer from 1 to 40, R 2 is -CH 2 CH(CO 2 -nBu)-, R 4 is TEMPO, and b is 1.0 ⁇ 0.3 mMol of poly (BA) per gram of insoluble solid support.)
  • a mixture of resin from Example 1 (100 mg, 100 ⁇ Mol), BA (0.6 mL, 4.19 mMol) and BuNCO (0.1 mL, 0.89 mMol) is flushed with nitrogen and heated in a septum capped tube at 130°C for 5 hours.
  • the cooled, wet polymeric mass is mixed with DCM (5 mL) and filtered.
  • the resin beads are washed with alternating portions of MeOH and DCM (five times each). After a final wash with MeOH. the beads are dried in a reduced pressure oven to afford 172 mg of solid-supported poly(BA).
  • EXAMPLE 10 Solid-supported Polv(BA)-Polv(Br-ST (A compound of Formula I wherein L is CH 2 , m is an integer from 1 to 40, p is zero, q is an integer from 1 to 100, R 1 is -CH 2 CH(CO -nBu)- R 2 is -CH CH(4-bromophenyl)-, R 4 is TEMPO, and b is 1.0 ⁇ 0.3 mMol of poly (BA)- poly(Br-ST) per gram of insoluble solid support.)
  • Solid-supported PolvfTMI-SD (A compound of Formula I wherein L is CH 2 , m is zero, w and p are one, q is an
  • R 2 is , R 3 is -CH 2 CH(Ph)-, R 4 is
  • Resins from Examples 5 and 11 are swelled in DCM (0.9 mL) and treated with 2-(4-bromophenyl)-ethylamine (0.1 mL, 0.64 mMol). The resulting mixtures are shaken in a capped vial for
  • EXAMPLE 14 Solid-supported PolvfMeST-ClCHo-ST ) (A compound of Formula I wherein L is CH 2 , m is zero, w and p are one, q is an integer from 1 to 40, R 2 is -CH C(CH 3 , Ph)-, R 3 is -CH 2 CH(3- and
  • R 4 is TEMPO
  • b is 1.0 ⁇ 0.3 mMol of poly (MeST- C1CH 2 -ST) per gram of insoluble solid support.
  • a mixture of resin prepared by the method of Example 1 (1.0 mMol N/g, 200 mg, 200 ⁇ Mol) , MeST (1.5 mL, 11.5 mMol) and C1CH 2 -ST (a mixture of
  • EXAMPLE 15 Solid-supported Polv(MeST-(3- and 4-(3-buten-l-yl-ST ⁇ )) (A compound of Formula I wherein L is CH , m is zero, w and p are one, q is an integer from 1 to 40, R 2 is -CH 2 C(CH 3 , Ph)-, R 3 is -CH 2 CH(3- and 4-(3-buten- l-yl)phenyl)-, R 4 is TEMPO, and b is 1.0 ⁇ 0.3 mMol of poly (MeST-(3- and 4- (3-buten-l-yl-ST))) per gram of insoluble solid support.)
  • EXAMPLE 16 Bromine Scavenging A solution of bromine (0.5 mMol) in DCM (5 mL) is chilled in an ice bath, treated with the resin from Example 15 (100 mg) and shaken for 15 minutes. The solution becomes colorless and the resin takes on a yellow color. Filtration of the polymer beads gives a colorless filtrate that yields no residue upon evaporation.
  • Solid-supported Polv(4-(l-isocvanatoethv styrene) (A compound of Formula I wherein L is CH 2 , m and p are zero, w is one, q is an integer from 1 to 100, R 2 is -CH 2 CH(4-(l-isocyanatoethyl)phenyl)-, R 4 is TEMPO, and b is 1.0 ⁇ 0.3 mMol of poly (TMI-BA) per gram of insoluble solid support.)
  • the resin from Example 1 50 mg, 50 ⁇ Mol N
  • the air in the tube is then purged by pressurizing and venting the tube with nitrogen or argon gas 20 times.
  • the septum-capped tube is then placed in an aluminum block which has been pre-heated to 130°C.
  • gentle mixing is optionally carried out by orbital shaking.
  • the resulting polymeric mass is cooled to room temperature and treated with dichloromethane (6 mL). The mixture is shaken for about an hour until all of the soluble polymer dissolves.
  • the insoluble beads are collected by filtration and subsequently rinsed alternately with dichloromethane and hexanes (five cycles of each solvent). After a final wash with hexanes, the insoluble beads are dried in a reduced pressure oven at 45°C for 6 hours to afford 400 mg of solid-supported poly(4-(l-isocyanatoethyl)styrene) which contains 5.0 mMol NCO/g.
  • R 2 is
  • R 4 is TEMPO ; and b is 1.0 ⁇ 0.3 mMol of poly (TMI-(4-l- isocyanatoethyl)styrene)) per gram of insoluble solid support.)
  • Resin from Example 1 200 mg, 0.2 mMol N
  • TMI (2 mL, 10.1 mMol) are placed in a septum-capped tube, and the tube is flushed with nitrogen.
  • the capped tube is heated at 130°C for 18 hours, then cooled to room temperature.
  • 4-(l-Isocyanatoethyl)-styrene) (760 mg, 4.4 mMol) is then added, and the tube is flushed with nitrogen.
  • the capped tube is then reheated at 130°C for 24 hours. After cooling to room temperature, the resulting wet polymeric mass is mixed with DCM (5 mL), and the resin beads are collected by filtration.
  • the beads are rinsed with alternating portions of DCM and hexanes (five times each). Drying in a reduced pressure oven at 45°C for 24 hours affords 850 mg of solid-supported poly(TMI- (4— ( 1 -isocyanatoethyl)styrene)) containing 4 mmol NCO/g.
  • Example 21 A portion of the resin from Example 21 (300 mg, 0.69 mMol) were placed in a dry 100 mL solid-phase paptide reaction vessel, cooled and purged under an atmosphere of N 2 , and l,3-dichloro-5,5-dimethylhydantoin (408 mg, 2.07 mMol, 3.0 equiv.) was added. Dry DCM (8 mL) was subsequently added, the vessel was placed on an orbital stirrer and the reaction was agitated at room temperature for 3 hours.
  • EXAMPLE 23 Solid-supported Polv(Me-ST-(H-DIPS-ST) (A compound of Formula I wherein L is CH 2 , m is zero, w and p are one, q is an integer from 1 to 50, R 2 is -CH 2 C(CH 3 , Ph)-, R 3 is -CH 2 CH(4- diisoproplsilyl)phenyl)-, R 4 is TEMPO and b is 1.0 ⁇ 0.3 mMol of poly(Me-ST- (H-DIPS-ST) per gram of insoluble solid support.
  • EXAMPLE 24 Solid-supported PolvfFs-ST .
  • a mixture of resin from Example 1 (1 mMol N/g, 150 mg, 150 ⁇ Mol), F 5 - ST (2.5 mL, 18 mMol) and m-tolyl isocyanate (75 ⁇ L, 570 ⁇ Mol) is flushed with nitrogen and heated at 130°C for 17.5 hours.
  • the cooled polymeric mass is treated with DCM (6 mL) and shaken for 10 minutes.
  • the suspension of beads is filtered and the beads are then washed with alternating portions of DCM and MeOH (five times each). After one final wash with MeOH, the beads are dried in a reduced pressure oven at 45-50°C overnight to afford 1.97 g of solid-supported poly(F 5 -

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Abstract

L'invention concerne des polymères fonctionnels et des amorceurs à support solide et aussi des procédés pour leur préparation et utilisation en phase de solution, en synthèse organique en phase solide et en chimie combinatoire comprenant l'utilisation comme amorceurs de polymérisation radicalires isolés à support solide, comme capteurs à support solide pour purifier des mélanges de réaction en phase de solution bruts, comme une phase stationnaire pour une synthèse organique en phase solide et comme des réactifs à support solide en synthèse organique en phase de solution.
PCT/US2000/017038 1999-06-23 2000-06-21 Amorceurs a support solide et polymeres fonctionnels utilises en synthese organique et chimie combinatoire WO2000078740A1 (fr)

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
WO2002079305A1 (fr) * 2001-03-28 2002-10-10 Polymerat Pty Ltd Procede de traitement de la surface d'un substrat polymere utilise dans la polymerisation par greffage
WO2004089857A2 (fr) * 2003-04-04 2004-10-21 Merck & Co., Inc. Synthese de polymeres fonctionnels destines a la synthese organique et a la chimie combinatoire
CN100439591C (zh) * 2004-06-30 2008-12-03 桂林正翰科技开发有限责任公司 一种接枝共聚进行离子交换纤维制备的新方法
US7881871B2 (en) 2003-12-12 2011-02-01 Bio-Layer Pty Limited Method for designing surfaces
US8168445B2 (en) 2004-07-02 2012-05-01 Bio-Layer Pty Limited Use of metal complexes
US8273403B2 (en) 2002-05-10 2012-09-25 Bio-Layer Pty Ltd. Generation of surface coating diversity

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DE19701665A1 (de) * 1997-01-18 1998-07-23 Knoell Hans Forschung Ev Methode zur Codierung in der kombinatorischen Chemie

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DE19701665A1 (de) * 1997-01-18 1998-07-23 Knoell Hans Forschung Ev Methode zur Codierung in der kombinatorischen Chemie

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D.J. GRAVERT ET AL.: "Soluble supports tailored for organic synthesis: Parallel polymer synthesis via sequential normal/living free radical processes", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 120, 1998, DC US, pages 9481 - 9495, XP002149956 *
J.C.HODGES ET AL: "Preparation of disigner resins via living free radical polymerization of functional monomers on solid support", JOURNAL OF COMBINATORIAL CHEMISTRY., vol. 2, no. 1, 2000 - 1980, AMERICAN CHEMICAL SOCIETY, WASHINGTON., US, pages 80 - 88, XP002149955, ISSN: 1520-4766 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002079305A1 (fr) * 2001-03-28 2002-10-10 Polymerat Pty Ltd Procede de traitement de la surface d'un substrat polymere utilise dans la polymerisation par greffage
US6858309B2 (en) 2001-03-28 2005-02-22 Polymerat Pty. Ltd. Methods of polymerization
US8273403B2 (en) 2002-05-10 2012-09-25 Bio-Layer Pty Ltd. Generation of surface coating diversity
WO2004089857A2 (fr) * 2003-04-04 2004-10-21 Merck & Co., Inc. Synthese de polymeres fonctionnels destines a la synthese organique et a la chimie combinatoire
WO2004089857A3 (fr) * 2003-04-04 2007-10-11 Merck & Co Inc Synthese de polymeres fonctionnels destines a la synthese organique et a la chimie combinatoire
US7592392B2 (en) 2003-04-04 2009-09-22 Merck & Co. Inc. Synthesis of functional polymers for use in organic synthesis and combinatorial chemistry
US7881871B2 (en) 2003-12-12 2011-02-01 Bio-Layer Pty Limited Method for designing surfaces
CN100439591C (zh) * 2004-06-30 2008-12-03 桂林正翰科技开发有限责任公司 一种接枝共聚进行离子交换纤维制备的新方法
US8168445B2 (en) 2004-07-02 2012-05-01 Bio-Layer Pty Limited Use of metal complexes

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