WO1998045231A1 - Supports pour synthese en phase solide - Google Patents

Supports pour synthese en phase solide Download PDF

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Publication number
WO1998045231A1
WO1998045231A1 PCT/US1998/007416 US9807416W WO9845231A1 WO 1998045231 A1 WO1998045231 A1 WO 1998045231A1 US 9807416 W US9807416 W US 9807416W WO 9845231 A1 WO9845231 A1 WO 9845231A1
Authority
WO
WIPO (PCT)
Prior art keywords
support
resin
solid
compound
solid support
Prior art date
Application number
PCT/US1998/007416
Other languages
English (en)
Inventor
Hui Shao
Arlindo L. Castelhano
Original Assignee
Cadus Pharmaceutical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadus Pharmaceutical Corporation filed Critical Cadus Pharmaceutical Corporation
Priority to AU71144/98A priority Critical patent/AU7114498A/en
Publication of WO1998045231A1 publication Critical patent/WO1998045231A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1836—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid
    • C07C273/1845—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid comprising the -N-C(O)-Hal moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • 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
    • 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
    • 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

  • the reaction can be performed at room temperature or, in certain embodiments, at elevated temperature (e.g., 80°C) to ensure completeness of reaction and to decrease reaction times.
  • the time required for the reaction can range from about one hour to 24 hours or more; an exemplary reaction time is 16 hours. This procedure has the advantage of requiring only a single synthetic step, using readily available reagents, and providing a substituted resin in good yield with simple purification.
  • carboxylic acids e.g., amino acids
  • tetrafluorophenolic cross-linked polystyrene resin e.g., as prepared in Example 1, infra
  • carboxylic acids esterified to tetrafluorophenolic cross-linked polystyrene resin can be cleaved from the resin by nucleophiles.
  • the reactivity of the ester bond is similar to the reactivity of the carboxylic acids esterified to the Kaiser oxime resin and to HMBA and sulfamylbenzoyl resins.
  • the tetrafluorophenolic cross-linked polystyrene resin of the invention should find use in many applications in which Kaiser resin, HMBA and sulfamylbenzoyl resins are currently used.
  • an immobilized amino acid can be deprotected, and subsequently reacted with a carbamoyl chloride to form an immobilized urea derivative, which is then cleaved from the solid support with amines to form urea derivatives of amino acid amides.
  • an immobilized amino acid can be deprotected, reductively aminated (e.g., with an aldehyde and a reducing agent), and cleaved from the solid support to provide amino acid amides in which the N-terminal amino group of the amino acid is substituted.
  • the reductive amination described in Example 5 occurs without substantial reduction of the resin or cleavage of the substrate compound from the resin.
  • the invention provides methods for the solid-supported combinatorial synthesis of libraries of compounds.
  • the method comprises the step of providing a substrate compound immobilized on a solid support of the invention (i.e., a tetrafluorophenol-substituted resin), and reacting the substrate compound with a reagent under conditions such that a library of compounds is formed.
  • a substrate compound immobilized on a solid support of the invention i.e., a tetrafluorophenol-substituted resin
  • the substrate compound i.e., a tetrafluorophenol-substituted resin
  • the substrate compound can be, e.g., an immobilized carboxylic acid (e.g., an amino acid), including a variegated population of carboxylic acids.
  • the reaction was monitored by FT-IR with a diffuse reflectance accessory (Perkin-Elmer Co.); the tetrafluorophenol group shows strong C-F absorption between 1 100 and 900 cm - 1 .
  • the mixture was stirred at 80°C for 16 hours, and the solvent was then removed by filtration via reduced pressure.
  • the resin was washed with several solvents to remove impurities: a wash with DMA was followed by a wash with 2-propanol: water (1 : 1, volume ratio), then 5% aqueous hydrogen chloride (HC1) solution, followed by methanol, and lastly dichloromethane (DCM). The washing procedure was repeated twice to ensure that impurities were removed.
  • the resin was dried over vacuum for 16 hours. Based on the results of microanalysis, the product resin contained 0.54 mmol of tetrafluorophenolic groups per gram of resin.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Structural Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des supports pour synthèse en phase solide. Lesdits supports comprennent une partie lieuse au phénol ou thiophénol. Un composé formant substrat peut être immobilisé sur le support par la partie lieuse. Lesdits supports conviennent à la synthèse combinatoire, dont la synthèse de bibliothèques combinatoires.
PCT/US1998/007416 1997-04-09 1998-04-09 Supports pour synthese en phase solide WO1998045231A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU71144/98A AU7114498A (en) 1997-04-09 1998-04-09 Supports for solid phase synthesis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83562397A 1997-04-09 1997-04-09
US08/835,623 1997-04-09

Publications (1)

Publication Number Publication Date
WO1998045231A1 true WO1998045231A1 (fr) 1998-10-15

Family

ID=25270004

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/007416 WO1998045231A1 (fr) 1997-04-09 1998-04-09 Supports pour synthese en phase solide

Country Status (2)

Country Link
AU (1) AU7114498A (fr)
WO (1) WO1998045231A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067228A1 (fr) 1998-06-24 1999-12-29 Aventis Pharmaceuticals Products Inc. Composes de resine de fluorophenyle
WO2000053545A1 (fr) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Procede de synthetisation de dihydropyridones
US6579725B1 (en) 1999-03-05 2003-06-17 Massachusetts Institute Of Technology Linkers for synthesis of oligosaccharides on solid supports

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1009905A (en) * 1962-05-02 1965-11-17 Rohm & Haas Redox polymers

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1009905A (en) * 1962-05-02 1965-11-17 Rohm & Haas Redox polymers

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D. L. MARSHALL: "A modified support for solid-phase peptide synthesis which permits the synthesis of protected peptide fragments", JOURNAL OF ORGANIC CHEMISTRY, vol. 35, no. 2, March 1970 (1970-03-01), EASTON US, pages 867 - 868, XP002073049 *
D. R. BARN: "Synthesis of an array of amides by aluminium chloride assisted cleavage of resin-bound esters", TETRAHEDRON LETTERS, vol. 37, no. 18, 1996, OXFORD GB, pages 3213 - 3216, XP002073048 *
M. FRIDKIN: "Use of polymers as chemical reagents. I Preparation of peptides", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 88, no. 13, 5 July 1966 (1966-07-05), DC US, pages 3164 - 3165, XP002073047 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067228A1 (fr) 1998-06-24 1999-12-29 Aventis Pharmaceuticals Products Inc. Composes de resine de fluorophenyle
EP1089988A1 (fr) * 1998-06-24 2001-04-11 Aventis Pharmaceuticals Products Inc. Composes de resine de fluorophenyle
EP1089988A4 (fr) * 1998-06-24 2005-01-19 Aventis Pharm Prod Inc Composes de resine de fluorophenyle
US6579725B1 (en) 1999-03-05 2003-06-17 Massachusetts Institute Of Technology Linkers for synthesis of oligosaccharides on solid supports
WO2000053545A1 (fr) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Procede de synthetisation de dihydropyridones

Also Published As

Publication number Publication date
AU7114498A (en) 1998-10-30

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