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EP1360211A2 - Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle - Google Patents

Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle

Info

Publication number
EP1360211A2
EP1360211A2 EP02703549A EP02703549A EP1360211A2 EP 1360211 A2 EP1360211 A2 EP 1360211A2 EP 02703549 A EP02703549 A EP 02703549A EP 02703549 A EP02703549 A EP 02703549A EP 1360211 A2 EP1360211 A2 EP 1360211A2
Authority
EP
European Patent Office
Prior art keywords
denotes
compounds
resin
alkyl
formula
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Withdrawn
Application number
EP02703549A
Other languages
German (de)
English (en)
Inventor
Enzo Cereda
Carlo Maria Pellegrini
Monica Quai
Walter Barbaglia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to EP02703549A priority Critical patent/EP1360211A2/fr
Publication of EP1360211A2 publication Critical patent/EP1360211A2/fr
Withdrawn legal-status Critical Current

Links

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
    • 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
    • C08F8/42—Introducing metal atoms or metal-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
    • C08G65/3331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group cyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/336—Polymers modified by chemical after-treatment with organic compounds containing silicon
    • 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

Definitions

  • the present invention relates to polymers characterised by novel silicon linkers based on the carbamyl piperazine moiety, methods of preparing these polymers and their use in the solid phase synthesis of compounds or libraries of compounds embracing a phenyl ring in their structure.
  • an hydrogen atom substitutes the silicon itself. Therefore the released compounds show no trace of the tethering point (in the hydrogen case) or show further diversity (when additional groups are inserted).
  • SPOC Solid phase organic chemistry
  • traceless linkers are those based on the silicon chemistry. These lead to a phenyl ring with no trace of the anchoring point owing to an ipso-desilylation process under acidic conditions (TFA) or to a fluoride mediated cleavage under basic conditions [tetrabuthyl ammonium fluoride (TB ⁇ F)]. According to a further option other non polar functionalities such as nitro, bromo or acetyl can be introduced, if desired, during the detachment step.
  • the general usefulness of the new linker is exemplified here by applying it on phenyl rings possessing functional groups such as hydroxy, formyl and amino, which can in turn, after deprotection, be derivatised.
  • a more complex pattern of substitution e.g. trifluoromethylpiperazine
  • Resin denotes polystyrene, optionally cross linked with divinyl benzene or polyethylenglycol
  • R 1 denotes hydrogen, C-j-Cg-alkyl, C ⁇ -Cg-alkenyl, C ⁇ -C ⁇ -alkynyl C ⁇ -CQ- alkoxy, halogen, NO2 or CF3
  • R2 denotes a group selected from hydroxy, amino, preferably
  • N-C-i-C ⁇ -alkylamino, and formyl being optionally protected by a suitable protective group, or a 5 or 6 membered saturated or unsaturated nitrogen heterocycle, optionally containing one or two additional heteroatoms selected from the group consisting. of oxygen, nitrogen and sulfur, and being optionally substituted by a group selected from Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, halogen,
  • Preferred polymers are those of general formula (I), wherein Resin denotes polystyrene, optionally cross linked with divinyl benzene or ⁇ polyethylenglycoi; . .
  • R denotes hydrogen, C ⁇ -C4-alk l, C-j-C4-alko.xy, fluorine, chlorine, bromine, or NO2;
  • R2 denotes a group selected from hydroxy, amino, preferably
  • -C4-alkylamino, and formyl being optionally protected by a suitable protective group, or a 5 or 6 membered saturated or unsaturated nitrogen heterocycle, optionally containing one additional nitrogen heteroatom which is substituted by a protective group selected from fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
  • More preferred polymers are those of general formula (I), wherein
  • Resin denotes polystyrene cross linked with divinyl benzene;
  • R 1 denotes hydrogen, methyl, methoxy , fluorine, chlorine, bromine, or NO2, preferably hydrogen;
  • R2 denotes hydroxy, being protected by a group selected from tertbutyldimethylsilyl, methoxy-ethoxymethyl (MEM) and methyl, or N-methylamino, being protected by a group selected from fluorenylmethyloxycarbonyl (FMOC) and t-butoxycarbonyl (BOC), or formyl, being protected to form a dioxolane ring, or piperazin-1-yl, being substituted by a protective group selected from fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
  • the term resin refers to polystyrene, optionally crosss linked with divinyl benzene, preferably with high swelling properties or highly cross linked macroporous polystyrene beads with low swelling capacity or cross linked ⁇ polystyrene - polyethylenglycol.
  • the preferred one. is a resin made with cross linked polystyrene - 1% divinylbenzene, 200-400 mesh of the so called Merrifield type. '
  • alkyl groups meant here are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as: methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl and hexyl.
  • Alkenyl groups are. the branched and unbranched alkenyl groups with 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least-one double bond, e.g. the alkyl groups mentioned above provided that they have at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are formed), propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.
  • alkenyl- and alkenylen-groups mentioned above are to be understood as embracing optionally existing stereoisomers. Accordingly, for . instance the definition 2-butenyl is to be understood as embracing 2-(Z)-butenyl and 2-(E)-butenyl, etc..
  • alkynyl groups refers to alkynyl groups having 2 to 6, preferably 2 to 4 carbon atoms provided that they have at least one triple bond, e.g. ethynyl, propargyl, butynyl, pentynyl and hexynyl.
  • amino denotes a group selected from H2, N-C-]-C6-alkylamino, preferably N-C- ⁇ -C-4-alkylamino, N-di(C ⁇ -C6-alkyl)amino, preferably N-di(C ⁇ -C-4-alkyl)amino, wherein C-i-Cg-alkyl is as hereinbefore defined.
  • Preferred aminogroups are selected from N-methylamino and N-ethylamino, preferably N-methylamino.
  • the suitable protective groups that are applicable according to the invention may differ depending on the functional group they protect.
  • the suitable protective group is preferably selected from methoxymethyl, benzyloxymethyl, t-butoxymethyl, tertbutyldimethylsilyl, tetrahydropyranyl, methoxyethoxyethyl and benzyl, preferred protecting group being tertbutyldimethylsilyl.
  • the suitable protective group is preferably selected from fluorenylmethyloxycarbonyl (FMOC), benzyloxycarbonyl, t- butoxycarbonyl (BOC), allyloxycarbonyl preferred protecting group being FMOC and BOC.
  • the formyl group is preferably protected by a protective group to form a group selected from 1 ,3-dioxolane, 1 ,3-dithiolane, preferred protecting group being 1 ,3- dioxolane.
  • 5- or 6-membered nitrogen heterocycles are as follows: piperazine, pyrrolidine, piperidine, morpholine, benzimidazole, benzoxazole, imidazole, pyrazole, preferably piperazine, morpholine, piperidine.
  • Halogen stands for fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
  • bromo-derivatives of formula (II) are obtainable via conventional methods known in the art. Those derivatives of formula (II) wherein R2 denotes a functional group being protected as hereinbefore defined are obtainable from the unprotected starting materials according to well known methods in the art, pertaining to the introduction of known protective groups. Starting from the appropriate bromo-derivatives of formula
  • the silyl-derivatives of formula (III) are available as follows. After activation by suitable organometallic reagents, preferably lithium alkyl reagents, more preferably branched or unbranched butyllithium reagents, at low temperature, preferably between -78°C and -20°C, most preferably between - 40 °C and - 60 °C, in an appropriate organic solvent, preferably in a solvent selected from the group consisting of tetrahydrofurane and diethylether, the dimethyl silyl bromomethyl chain is introduced to by addition of the appropriate chlorosilane to generate compound of formula (III). To obatin the compounds of formula (IV) on the compounds of formula
  • a piperazine spacer is added by reaction with excess piperazine or using a Fmoc or Boc monoprotected piperazine in the presence of a base selected from the group triethylamine, pyridine, diisopropylethylamine, with diisopropylethylamine being the most preferred base to catch the generated acid.
  • the reaction is preferably conducted under heating, preferably between 40-120°C, more preferred between 60- 100°C in an organic solvent selected from the group consisting of dimethylsulfoxide, N-methyl-pyrrolidone (NMP), ethanol wherein dimethylsulfoxide is most preferred.
  • the compounds of formula (I) are obtained by reacting a slight excess (1.5 equivalent) of the compounds of formula (IV) with a polymeric resin being functional ized by isocyanate-groups.
  • the reaction is preferably conducted in an apolar solvent selected from the group consisting of tetrahydrofurane, DMF, dichloromethane, with tetrahydrofurane being the most preferred solvent at moderate temperatures (between 0-40°C, preferably between 20-30°C).
  • a base preferably of an organic base selected from the amines mentioned hereinbefore may be advisable.
  • the most preferred base is disiopropylethylamine.
  • R1 denotes hydrogen, C-i-C ⁇ -alkyl, C2-C6-alkenyl, C2-C6-alkynyI C-i-C ⁇ - alkoxy, halogen, NO2 or CF3;
  • R 2 denotes a group selected from hydroxy, amino, preferably
  • N-C-i-C ⁇ -alkylamino, and formyl being optionally protected by a suitable protective group, or a 5 or 6 membered saturated or unsaturated nitrogen heterocycle, optionally containing one or two additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and being optionally substituted by a group selected from Ci-C -alkyl, C-j-C ⁇ -alkoxy, halogen,
  • Preferred intermediates are those of general formula (IV), wherein R1 denotes hydrogen, C-j-C-4-alkyl, C-
  • -C4-alkylamino, and formyl being optionally protected by a suitable protective group, or a 5 or 6 membered saturated or unsaturated nitrogen heterocycle, optionally containing one additional nitrogen heteroatom which is substituted by a protective group selected from fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
  • a protective group selected from fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
  • Rl denotes hydrogen, methyl, methoxy , fluorine, chlorine, bromine, or NO2, preferably hydrogen;
  • R2 denotes hydroxy, being protected by a group selected from tertbutyldimethylsilyl, methoxy-ethoxymethyl (MEM) and methyl, or
  • N-methylamino being protected by a group selected from fluorenylmethyloxycarbonyl (FMOC) and t-butoxycarbonyl (BOC), or formyl, being protected to form a dioxolane ring, or piperazin-1-yl, being substituted by a protective group selected from fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
  • FMOC fluorenylmethyloxycarbonyl
  • BOC t-butoxycarbonyl
  • formyl being protected to form a dioxolane ring
  • piperazin-1-yl being substituted by a protective group selected from fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
  • R 2 denotes a suitably protected hydroxy, amino or formyl group
  • R 2 denotes a suitably protected hydroxy, amino or formyl group
  • the methods for the cleavage of the protective groups being applicable according to the invention are well known in the art. After cleavage of the protective group the hydroxy, amino. or formyl group can be further derivatised via conventional methods to lead to compounds of formula (I')
  • Resin and Rl are as hereinbefore defined and
  • R 3 denotes a group selected from -O-CO-C-
  • the compounds of formula (I) (or (I')) can be easily cleaved from the resin under mild reaction conditions to lead to the products of formula (V) (scheme 2).
  • X may either denote hydrogen, halogens (Br, F, I) or -COMe.
  • Compounds (V) wherein X denotes hydrogen are obtainable by reacting compounds of formula (1) or (I') with tetrabutylammonium fluoride (TBAF), Cesium fluoride, KF, trifluoroacetic acid or triflic acid, preferably with TBAF under the reaction conditions that are usually applied for analogous cleavage reactions known in the art.
  • TBAF tetrabutylammonium fluoride
  • Cesium fluoride KF
  • trifluoroacetic acid or triflic acid preferably with TBAF under the reaction conditions that are usually applied for analogous cleavage reactions known in the art.
  • the crude compound was purified by flash chromatography (Silica-gel, eluent n- hexane-ethyl acetate 90-10).
  • the compound was pure enough to be used in the following step, without further characterization.
  • the resin bound compound was obtained starting from 150 mg of (isocyanate)- polystyrene resin. 150 mg, yellowish resin 1 H-NMR (solid state; gel phase in CD 2 CI 2 ; 300 MHz) 5.72 (1 H); 3.9-4.1 (4h); 3.26 (4H); 2.31 (4H); 2.16 (2H); 0.37 (6H)
  • the resin bound compound was obtained starting from 300 mg of (isocyanate)- polystyrene resin. 300 mg, resin
  • the resin bound compound was obtained starting from 1 g of (isocyanate)- polystyrene resin. 1 g, resin

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Structural Engineering (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

La présente invention porte sur des polymères qui se caractérisent par de nouveaux lieurs de silicium à base de la fraction carbamyle pipérazine, sur des procédés de préparation de ces polymères et sur leur utilisation dans la synthèse en phase solide de composés ou bibliothèques de composés renfermant un noyau phényle dans leur structure.
EP02703549A 2001-01-29 2002-01-15 Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle Withdrawn EP1360211A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02703549A EP1360211A2 (fr) 2001-01-29 2002-01-15 Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP01101946 2001-01-29
EP01101946 2001-01-29
EP02703549A EP1360211A2 (fr) 2001-01-29 2002-01-15 Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle
PCT/EP2002/000312 WO2002060960A2 (fr) 2001-01-29 2002-01-15 Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle

Publications (1)

Publication Number Publication Date
EP1360211A2 true EP1360211A2 (fr) 2003-11-12

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02703549A Withdrawn EP1360211A2 (fr) 2001-01-29 2002-01-15 Nouveaux polymeres a base de lieurs sans trace n-carbamyl-n'-dimethylsilyl methyl-piperazine pour la synthese en phase solide de bibliotheques a base phenyle

Country Status (5)

Country Link
EP (1) EP1360211A2 (fr)
JP (1) JP2004518015A (fr)
CA (1) CA2431927A1 (fr)
MX (1) MXPA03006718A (fr)
WO (1) WO2002060960A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102122470B1 (ko) 2016-12-08 2020-06-12 주식회사 엘지화학 변성제 및 이로부터 유래된 작용기를 포함하는 변성 공액디엔계 중합체

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2213825T3 (es) * 1996-05-20 2004-09-01 Smithkline Beecham Corporation Engarce sililo para sintesis organica en fase solida de moleculas que contienen arilo.
WO1999017869A2 (fr) * 1997-10-03 1999-04-15 Argonaut Technologies Compositions de synthese organique en phase solide et leurs methodes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02060960A3 *

Also Published As

Publication number Publication date
CA2431927A1 (fr) 2002-08-08
WO2002060960A3 (fr) 2002-10-17
WO2002060960A2 (fr) 2002-08-08
MXPA03006718A (es) 2004-05-31
JP2004518015A (ja) 2004-06-17

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