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WO1999039207A1 - Linker phenoxyalkyle clivable par un acide pour synthese combinatoire - Google Patents

Linker phenoxyalkyle clivable par un acide pour synthese combinatoire Download PDF

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Publication number
WO1999039207A1
WO1999039207A1 PCT/US1999/001370 US9901370W WO9939207A1 WO 1999039207 A1 WO1999039207 A1 WO 1999039207A1 US 9901370 W US9901370 W US 9901370W WO 9939207 A1 WO9939207 A1 WO 9939207A1
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Prior art keywords
lower alkyl
substrate
solid phase
formula
phenyl
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.)
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PCT/US1999/001370
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English (en)
Inventor
Ge Li
Zhen Min He
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Pharmacopeia LLC
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Pharmacopeia Inc
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Filing date
Publication date
Application filed by Pharmacopeia Inc filed Critical Pharmacopeia Inc
Priority to AU23358/99A priority Critical patent/AU2335899A/en
Publication of WO1999039207A1 publication Critical patent/WO1999039207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B80/00—Linkers or spacers specially adapted for combinatorial chemistry or libraries, e.g. traceless linkers or safety-catch linkers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • C07K1/042—General 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
    • 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
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C40B50/18—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support using a particular method of attachment to the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • This invention relates generally to the synthesis of chemical compounds, and more particularly, to the solid phase synthesis of combinatorial libraries of chemical compounds.
  • Combinatorial organic synthesis is becoming an important tool in drug discovery. Methods for the synthesis of large numbers of diverse compounds have been described [EUman, et. al. Chem. Rev. 96: 555-600 (1996)], as have methods for tagging systems [Ohlmeyer et al, Proc. Natl. Acad. Sci. USA, 90, 10922- 10926, (1993)].
  • the growing importance of combinatorial synthesis has created a need for new resins and linkers having chemical and physical properties to accommodate a wide range of conditions, since success depends on the ability to synthesize diverse sets of molecules on a solid support and to then cleave those molecules cleanly and in good yield.
  • Linkers are molecules that can be attached to a solid support and to which the desired members of a library of chemical compounds may in turn be attached. When the construction of the library is complete, the linker allows clean separation of the target compounds from the solid support without harm to the compounds and preferably without damage to the support.
  • Several linkers have been described in the literature. Their success relies on having sufficient stability to allow the steps of combinatorial synthesis under conditions that will not cleave the linker, while still having a fairly high lability under at least one set of conditions that is not employed in the synthesis. For example, if an acid labile linker is employed, then the combinatorial synthesis must be restricted to reactions that do not require the -2-
  • the 4-[4-(hydroxymethyl)-3-methoxyphenoxy]butyryl residue is a known linker, which is attached to a solid support having amino functionalities by forming an amide with the carboxyl of the butyric acid chain.
  • N-Protected amino acids are attached to the hydroxyl of the 4-hydroxymethyl group via their carboxyl to form 2,4-dialkoxybenzyl esters, which can be readily cleaved in acid media when the synthesis is complete [see for example Riniker et al. Tetrahedron 49 9307-9312 (1993)].
  • the drawback to such esters is that they can also be cleaved by many of the reagents that one might want to use in combinatorial synthesis.
  • ester is formed from 4-[4- (hydroxymethyl)phenoxy]butyric acid. It has been described in European published application EP 445915. In this case, the ester was cleaved with a 90:5:5 mixture of trifluoroacetic acid, dimethyl sulfide and thioanisole.
  • the 4-[4-(formyl)-3,5- dimethoxyphenoxy]butyryl residue has been employed. It is attached to a solid phase substrate via the carboxyl of the butyric acid chain, and the 4-aldehyde is reductively aminated. N-Protected amino acids are then reacted with the alkylamine via their carboxyl to form 2,4,6-trialkoxybenzylamides. These may be cleaved by 1: 1 trifluoroacetic acid in dichloromethane. [See PCT application WO97/23508.]
  • the present invention relates to a linker-resin combination that demonstrates the ability to withstand many of the common reaction conditions and is cleavable to release a phenol under conditions that do not diminish the chemical integrity of the desired products.
  • the invention relates to a substrate for solid phase synthesis comprising a solid phase-linker combination of the formula:
  • X is bromo, chloro, mesylate or tosylate, and n is 3-20, preferably 3-5.
  • Preferred solid phases are aminomethylated poly(styrene-co- divinylbenzene) and divinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrene functionalized with amino groups.
  • X is bromo.
  • the invention relates to chemical intermediates of the formula
  • R 2 is lower alkyl or phenyl; and R 3 is lower alkyl, phenyl or lower alkoxy. In preferred embodiments R 1 and R 2 are methyl and R 3 is t-butyl.
  • the invention relates to processes for preparing the foregoing substrate for solid phase synthesis.
  • One process comprises: (a) combining the foregoing chemical intermediate, in which R is OH, and the solid support having amino functionality in an inert solvent in the presence of condensing agents to provide a silylated precursor of a substrate for solid phase synthesis of formula
  • R 3 wherein R is the residue of the amino functional solid support; (b) treating the silylated precursor with a reagent capable of cleaving a silyl ether to provide a benzyl alcohol precursor of a substrate for solid phase synthesis; and (c) treating the benzyl alcohol precursor with an excess of a brominating reagent in an inert solvent to provide the substrate for solid phase synthesis.
  • a subset of R namely R 4
  • R 4 is a group displaceable by an amine and no condensing agent is needed.
  • R 4 will be an activated ester.
  • the reagent capable of cleaving a silyl ether is a tetraalkylammonium fluoride and the brominating reagent is phosphorus tribromide.
  • the invention relates to a process for preparing a compound of formula o
  • the lower alkyl ⁇ -haloalkylcarboxylate is ethyl 4-bromobutyrate
  • the alkali metal carbonate is cesium carbonate
  • the silylating agent is a combination of t-butyldimethylsilyl chloride and imidazole
  • the alkali metal hydroxide is lithium hydroxide.
  • Boc t-butyloxy carbonyl
  • DIEA N,N-diisopropylethyl amine
  • EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
  • HATU O-(7- Azabenzotriazol- 1 -yl)- 1,1,3,3 -tetramethyluronium hexafluorophosphate
  • HOBt hydroxybenzotriazole
  • NMO N-methylmorpholine oxide
  • PEG polyethylene glycol
  • Ph phenyl -7-
  • Alkyl is intended to include linear, or branched hydrocarbon structures and combinations thereof of 1 to 20 carbons.
  • Lower alkyl means alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl, pentyl, hexyl, and the like.
  • Cycloalkyl refers to saturated hydrocarbons of from 3 to 12 carbon atoms having one or more rings.
  • Examples of “cycloalkyl” groups include c-propyl, c- butyl, c-pentyl,c-hexyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentylmethyl, norbornyl, adamantyl, myrtanyl and the like.
  • “Lower cycloalkyl” refers to cycloalkyl of 3 to 6 carbons.
  • Ci to C 20 Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include phenethyl, cyclohexylmethyl and naphthylethyl.
  • Alkoxy means alkoxy groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • “Lower alkoxy” means alkoxy having 1-4 carbon atoms.
  • Halo includes F, Cl, Br, and I.
  • Fluoroalkyl refers to an alkyl residue in which one or more hydrogen atoms are replaced with F, for example: trifluoromethyl, difluoromethyl, and pentafluoroethyl.
  • Arylalkyl denotes a residue comprising an alkyl attached to an aryl ring.
  • Examples include benzyl, phenethyl, 4-chlorobenzyl, and the like.
  • combinatorial library means a collection of molecules based on logical design and involving the selective combination of building blocks by means of simultaneous chemical reactions.
  • Each species of molecule in the library is referred to as a member of the library.
  • the linkers of the invention could be used in combinatorial synthesis to attach tags as well as to attach the moiety of putative chemical or pharmacological interest.
  • Tags are chemical entities which possess several properties: they are detachable from the solid supports, preferably by means orthogonal to those employed for releasing the compound of pharmacological interest; they are stable under the synthetic conditions; and they are capable of being detected at very low concentrations, e.g., 10 "18 to 10 "9 mole. Suitable tags and methods for their employment are described in US patent 5,565,324, the entire disclosure of which is incorporated herein by reference. -9-
  • solid supports The materials upon which the combinatorial syntheses are performed are referred to as solid supports, beads, and resins. These terms are intended to include:
  • beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bis- acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, etc., i.e., material having a rigid or semi-rigid surface; and (b) soluble supports such as polyethylene glycol or low molecular weight, non-cross-linked polystyrene.
  • the solid supports may, and usually do, have surfaces that have been functionalized with amino, hydroxy, carboxy, or halo groups; amino groups are most common.
  • Techniques for functionalizing the surface of solid phases are well known in the art. Attachment of lysine to the surface of a bead (to increase the number of available sites) and subsequent attachment of linkers as well as further steps in a typical combinatorial synthesis are described, for example, in PCT application WO95/30642, the disclosure of which is incorporated herein by reference. In the synthesis described in WO95/30642, the linker is a photolytically cleavable linker, but the general principles of the use of a linker are well illustrated.
  • the invention relates to substrates for solid phase synthesis comprising solid phase-linker combinations of the formula:
  • X is preferably bromo because it is most easily introduced and it reacts more rapidly and cleanly with phenols, but chloro, mesylate or tosylate could be used.
  • the solid phase-linker combination is prepared by coupling an aminomethylated resin with a chemical intermediate of the formula -10-
  • R 1 is lower alkyl or phenyl
  • R 2 is lower alkyl or phenyl
  • R 3 is lower alkyl, phenyl or lower alkoxy.
  • R 1 and R 2 are methyl and R 3 is t-butyl, but any of the well known silyl ether protecting groups can be employed. [See Greene and Wuts Protective Groups in Organic Synthesis Second Edition John Wiley & Sons, New York 1991, pages 68-86, which are incorporated herein by reference.].
  • the coupling involves (a) combining the foregoing chemical intermediate and the aminomethylated solid support in an inert solvent such as dichloromethane, THF or DMF, in the presence of condensing agents to provide a silylated precursor of a substrate for solid phase synthesis of formula
  • R is the aminomethylated solid support; (b) treating the silylated precursor with a reagent capable of cleaving a silyl ether so as to provide a benzyl alcohol precursor of a substrate for solid phase synthesis; and (c) treating the benzyl alcohol with an excess of a brominating reagent in an inert solvent to provide the substrate for solid phase synthesis.
  • a reagent refers to one or more substances that effect a chemical change.
  • a reagent may comprise a single component, for example, phosphorus tribromide, or a plurality of components, for example, a combination of trimethylsilyl chloride and imidazole.
  • Condensing agents for reacting amines (the resin) with carboxylic acids (the linker) are well known, particularly in the art of solid phase synthesis of peptides.
  • Such agents include carbodiimides of various sorts, EEDQ, HATU, and the like. It is also possible to pre-react the carboxylic acid of the linker with an appropriate leaving group to form an activated ester.
  • Activated esters denote esters which are capable of undergoing a substitution reaction with primary or secondary amines to form an amide. The term includes esters "activated" by neighboring electron withdrawing substituents.
  • esters of phenols particularly electronegatively substituted phenol esters such as pentafluorophenol esters; O- esters of isourea, such as arise from interaction with carbodiimides; O-esters of N- hydroxyimides and N-hydroxy heterocycles; specific examples include S-t-butyl esters, S-phenyl esters, S-2-pyridyl esters, N-hydroxypiperidine esters, N- hydroxysuccinimide esters, N-hydroxyphthalimide esters and N- hydroxybenzotriazole esters.
  • the reagent capable of cleaving a silyl ether can be any of those described in
  • the ether may be cleaved by anhydrous fluoride ion, which may be provided by a tetraalkylammonium fluoride, such as tetrabutyl ammonium fluoride, in an anhydrous solvent, such as THF.
  • anhydrous fluoride ion which may be provided by a tetraalkylammonium fluoride, such as tetrabutyl ammonium fluoride
  • THF tetrabutyl
  • Many other cleavage reagents are known for TBDMS and are possible [See Greene and Wuts, op.cit. p. 80-81.]
  • the hydroxyl of the benzyl alcohol may be replaced with bromine by treatment with phosphorus tribromide, as described below, or by carbon tetrabromide and a trivalent phosphorus reagent, such as triphenyl phosphine.
  • phosphorus tribromide as described below
  • carbon tetrabromide and a trivalent phosphorus reagent such as triphenyl phosphine.
  • Other residues that can be readily displaced by a phenol may also replace the hydroxyl.
  • chlorine may be introduced in an analogous fashion to that employed for bromine.
  • the mesylate and tosylate residues may be introduced by treatment of the hydroxyl with methanesulfonyl chloride or toluenesulfonyl chloride respectively. These and other methods are well known in the art. -12-
  • Lower alkyl ⁇ -haloalkylcarboxylates are readily prepared by procedures known in the art, and most of those in the C-4 to C-10 range are commercially available.
  • the lower alkyl ⁇ -haloalkylcarboxylate is ethyl 4-bromobutyrate. It is desirable to employ a base in the reaction of the haloalkylcarboxylate with the phenol.
  • Alkali metal carbonates are simple to use and cheap, but other bases could be used, including organic bases.
  • a preferred alkali metal carbonate is cesium carbonate.
  • silylating conditions that we have employed are excess t- butyldimethylsilyl chloride in the presence of excess imidazole, but other conditions are described in Greene and Wuts and could be used. Many silylations, particularly those with silyl chlorides, are best run in the presence of at least one equivalent of a weak base. -13-
  • Saponification of the lower alkyl ester may be accomplished most cleanly with lithium hydroxide, but other alkali metal hydroxides could also be used and the pH may be controlled, e.g. by means of an autotitrator.
  • the invention relates to a process for preparing a substrate for solid phase synthesis of the formula:
  • n is 3-5 comprising
  • the invention relates to a process for preparing a compound of formula
  • the solid phase-linker combination may be reacted with a phenol in the presence of a base.
  • Alkali metal carbonates are simple to use and cheap, but other bases could be used, including organic bases.
  • a preferred alkali metal carbonate is cesium carbonate, which is slurried with the resin and phenol in an inert solvent such as DMF.
  • the linker can be cleaved from the resin by treatment with 50% trifluoroacetic acid in dichloromethane.
  • Ethyl-4-(p-hydroxymethyl)phenoxybutyrate(I) 4-Hydroxybenzyl alcohol( 12.4g, 0.1 mole) in 100 mL DMF was treated at room temperature with ethyl 4- bromobutyrate (19.5g, 0.1 mole) followed by adding cesium carbonate (32.6g, 0. Imole). The reaction proceeded for 3 hours and was poured into 300 mL of ethyl acetate. The organic layer was washed with water (50mL x 2) and brine (50mL x 1), and dried over anhydrous sodium sulfate. About 4g clear oil was obtained after removal of solvent. This crude oil was quite pure, as shown by proton NMR, and was used for the next step without purification.
  • the resin was washed with DMF (50 mL, 2x), MeOH(50 mL, lx), CH 2 Cl 2 (50mL,3x), and THF(50mL, lx). Bromophenol blue test on the completely dried resin showed a colorless result.
  • the resin was shaken with 1 M tetrabutylammonium fluoride in THF(40 mL) for 3 hours, and then washed with CH 2 C1 2 (50 mL,2x), MeOH(50 mL, 3x), and THF (50mL, lx). The resin was dried and stored in a freezer.

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention porte sur un substrat pour synthèse en phase solide de la formule (I); sur des procédés de préparation du substrat et des intermédiaires utiles. Parmi ces intermédiaires, on trouve des composés de la formule (II) dans laquelle n vaut entre 3 et 20; R représente OH, un ester activé ou les reste d'un support solide ayant une pluralité de fonctionnalités amino; R1 représente alkyle inférieur ou phényle; R2 représente alkyle inférieur ou phényle; et R3 représente alkyle inférieur, phényle ou alcoxy inférieur.
PCT/US1999/001370 1998-01-29 1999-01-21 Linker phenoxyalkyle clivable par un acide pour synthese combinatoire Ceased WO1999039207A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU23358/99A AU2335899A (en) 1998-01-29 1999-01-21 Acid cleavable phenoxyalkyl linker for combinatorial synthesis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1528298A 1998-01-29 1998-01-29
US09/015,282 1998-01-29

Publications (1)

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WO1999039207A1 true WO1999039207A1 (fr) 1999-08-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070567A1 (fr) * 2001-03-07 2002-09-12 Japan Represented By President Of Tokyo Institute Of Technology Compose, procede d'elaboration, et utilisation comme support de reaction en phase solide
US6579725B1 (en) 1999-03-05 2003-06-17 Massachusetts Institute Of Technology Linkers for synthesis of oligosaccharides on solid supports

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445915A1 (fr) * 1990-02-02 1991-09-11 Akademie Ved Ceske Republiky Méthode pour effectuer la synthèse de plusieurs peptides sur un support solide et appareillage pour exécuter cette méthode
EP0689845A2 (fr) * 1994-06-03 1996-01-03 American Cyanamid Company Conjugaison d'agents méthyltrithio antitumoraux et leurs intermédiaires de synthése

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445915A1 (fr) * 1990-02-02 1991-09-11 Akademie Ved Ceske Republiky Méthode pour effectuer la synthèse de plusieurs peptides sur un support solide et appareillage pour exécuter cette méthode
EP0689845A2 (fr) * 1994-06-03 1996-01-03 American Cyanamid Company Conjugaison d'agents méthyltrithio antitumoraux et leurs intermédiaires de synthése

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FRANK et al., "Simultaneous Multiple Peptide Synthesis Under Continuous Flow Conditions on Cellulose Paper Disks as Segmental Solid Supports", TETRAHEDRON, 1988, Vol. 44, No. 19, pages 6031-6040. *
GREENE THEODORA W. and WUTS PETERS G., Protective Groups in Organic Synthesis, 2nd Ed., NEW YORK: JOHN WILEY & SONS, INC., 1991, pages 10-87. *
NGU et al., "Preparation of Acid-Labile Resins with Halide Linkers and Their Utility in Solid Phase Organic Synthesis", TETRAHEDRON LETTERS, 22 September 1997, Vol. 38, No. 6, pages 973-976. *
RINIKER et al., "A General Strategy for the Synthesis of Large Peptides: The Combined Solid-Phase and Solution Approach", TETRAHEDRON, 08 October 1993, Vol. 49, No. 41, pages 9307-9320. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6579725B1 (en) 1999-03-05 2003-06-17 Massachusetts Institute Of Technology Linkers for synthesis of oligosaccharides on solid supports
WO2002070567A1 (fr) * 2001-03-07 2002-09-12 Japan Represented By President Of Tokyo Institute Of Technology Compose, procede d'elaboration, et utilisation comme support de reaction en phase solide

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