WO2003051795A2 - Isonitriles lies a la resine - Google Patents

Isonitriles lies a la resine Download PDF

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Publication number
WO2003051795A2
WO2003051795A2 PCT/EP2002/014386 EP0214386W WO03051795A2 WO 2003051795 A2 WO2003051795 A2 WO 2003051795A2 EP 0214386 W EP0214386 W EP 0214386W WO 03051795 A2 WO03051795 A2 WO 03051795A2
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WO
WIPO (PCT)
Prior art keywords
resin
compounds
group
compounds according
carboxylic acid
Prior art date
Application number
PCT/EP2002/014386
Other languages
German (de)
English (en)
Other versions
WO2003051795A3 (fr
Inventor
Bernd Henkel
Original Assignee
Morphochem Ag
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 Morphochem Ag filed Critical Morphochem Ag
Priority to AU2002358734A priority Critical patent/AU2002358734A1/en
Publication of WO2003051795A2 publication Critical patent/WO2003051795A2/fr
Publication of WO2003051795A3 publication Critical patent/WO2003051795A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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

Definitions

  • the present invention relates to new polymer-bound isocyanide derivatives, processes for their preparation and their use for the synthesis of heterocycles and of substance libraries.
  • Isocyanides are important starting materials for the synthesis of biologically active products. Since they serve as starting materials in multicomponent reactions (MCR), they are suitable for the rapid and efficient synthesis of large substance libraries (A. Dömling, I. Ugi, Angewandte Chemie, 2000, (112), 3300-3344).
  • MCR multicomponent reactions
  • synthesis on polymer-bound supports solid-phase synthesis
  • excess reagents can be used and the product can be cleaved from the resin in good yields at the end of the synthesis sequence.
  • the polymer-bound isocyanides known to date are not of general and wide breadth and are comparatively cumbersome and sequential to synthesize over many steps.
  • the object of the present invention was therefore to provide new polymer-bound derivatives of an isonitrile described by Schöllkopf (U. Schöllkopf et al. Liebigs Ann. Chem. 1979, 1444-1446), which are particularly suitable for the synthesis of heterocycles.
  • the present invention relates to new polymer-bound isonitriles of the general formula (I):
  • Pol is a carrier
  • L is a linker or a direct bond
  • R is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or a heteroaralkyl radical, and
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, Isobutyl, tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom (preferably oxygen or nitrogen), e.g. an alkyloxy group such as e.g. Methoxy or ethoxy, or a methoxymethyl, nitrile, methylcarboxyalkyl ester, carboxyalkyl ester or 2,3-dioxyethyl group.
  • heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acyloxy, carboxyalkyl, carboxyalkyl esters e.g. Methyl carboxyalkyl ester, carboxyalkyl amide, alkoxycarbonyl or alkoxycarbonyloxy.
  • cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic group which has one or more rings which form a skeleton which has 3 to 14 carbon atoms, preferably 3 contains up to 10 carbon atoms, for example the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.
  • heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus or sulfur atom and can be used, for example, for piperidine -, Morpholine, N-methylpiperazine or N-phenyl-piperazine group.
  • alkylcycloalkyl or heteroalkylcycloalkyl refer to groups which, in accordance with the above definitions, contain both cycloalkyl or heterocycloalkyl and also alkyl, alkenyl, alkynyl and / or heteroalkyl groups.
  • aryl or Ar refers to an aromatic group which has one or more rings and is formed by a skeleton which contains 5 or 6 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms, e.g. a phenyl, naphthyl, biphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxy-p enyl group.
  • heteroaryl refers to an aryl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus or sulfur atom, e.g. the 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl group.
  • aralkyl or heteroaralkyl refer to Groups which contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups, for example the tetrahydroisoquinolinyl, benzyl, in accordance with the above definitions -, 2- or 3-ethylindolyl or 4-methylpyridino group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups are represented by fluorine, chlorine or bromine or iodine atoms or OH, SH, NH 2 or N0 2 groups are replaced.
  • Compounds of formula (I) may contain one or more centers of chirality due to their substitution.
  • the present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • the present invention also encompasses all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof.
  • linker refers to a chemical group that is suitable for connecting molecules to the carrier.
  • the linker is a chemical structural unit that is covalently bound to the solid support on the one hand and covalently to the U group on the other. Due to the linker, the target molecule can be completed synthesis under gentle conditions again cleaved from the carrier. Depending on the synthesis strategy, it is possible that part of the linker becomes part of the target compound during the cleavage.
  • a linker can be an alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aralkylene or a heteroaralkylene group. Examples of linkers are found in P.
  • Examples include the trityl linker (optionally substituted in the 2-position by a chlorine atom or in the 4-position by a methyl or methoxy group), the Wang linker, the SASRIN TM linker, the Rink acid linker, the benzhydryl alcohol -Linker, the HMBA linker and polymeric benzyl halide (linker of the Merrifield resin) and the P7 ⁇ M linker.
  • the Wang Linker, the Trityllinker, the Merrifield Linker and the HMBA Linker are preferred.
  • carrier refers to a polymer (preferably a chemically inert polymer) that has been modified for organic solid phase synthesis so that chemical substances can be covalently bound to it.
  • polymeric supports are described in P. Seneci, Solid-Phase Synthesis and Combinatorial Technologies, John Wiley & Sons, New York, 2000; D. Obrecht and JM Villalgordo, Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Tetrahedron Organic-Chemistry Series Volume 17, Elsevier Science Ltd, Oxford, 1998 and in F. Z. Dörwald, Organic Synthesis on Solid Phase, Wiley-VCH, Weinheim, 2000. A distinction is made between soluble and insoluble polymeric carriers.
  • soluble polymeric carriers are the polyethylene glycols (PEG).
  • insoluble polymeric supports are polymers based on polystyrene (crosslinked with divinylbenzene) such as B. the Merrifield resin, bromo- (4-methoxyphenyl) methyl polystyrene, 4- (bromomethyl) phenoxyethyl polystyrene, the 2-chlorotrityl resin, tentacle polymers such as Tentagel®, silica gel, controlled pore glass (CPG), cellulose, copolymers and gold.
  • Polymeric carriers are available from a number of companies such as B.
  • Preferred carriers are polystyrene (crosslinked with up to 3% divinylbenzene (preferably 1-2% DVB), polyethylene glycol derivatives and tentacle polymers (in particular Tentagel®).
  • Preferred compounds of the general formula (I) are those in which X is a group of the formula -NR -'- R 2 or -0R 3 , where R 1 , R 2 and R 3 are preferably Ci-C ⁇ -alkyl groups or R 1 and R 2 together are part of a heterocycloalkyl ring system with 5 to 7 ring atoms; X is particularly preferably a group of the formula -NMe 2
  • Pol-L- preferably have one of the following structures:
  • PS is a cross-linked polystyrene with up to 3% DVB (preferably 1-2%).
  • PS polyethylene glycol with different chain lengths
  • tentacle polymer in particular Tentagel®
  • linker systems the one Have leaving group which can form a salt with alkali or alkaline earth anions of isocyanoacetic acid (e.g. chloride, bromide or tosylate).
  • the compounds of the general formula (I) can be prepared in a two-stage process.
  • an isocyanoacetic acid salt (III) is coupled to a resin (II).
  • Shark is a halogen atom (preferably chlorine or bromine)
  • M an alkali metal ion, an ammonium ion or an alkaline earth metal ion (preferably potassium)
  • R 5 is an alkyl group (preferably methyl or ethyl).
  • the compounds of the general formula (I) according to the invention can be used for the synthesis of oxazole, thiazole, imidazole, tetrazole and piperazine derivatives.
  • the compounds of the general formula (I) according to the invention for the solid phase synthesis of heterocycles of the formulas (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XIII ), the radicals R a , R b , R c , R d , R ⁇ , R f , R s and R h independently of one another an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl -, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl radicals, or two of the radicals R, R b , R °, R d , R e , R f , R g and R h optionally part of an aryl , Heteroaryl, cycloalkyl, heterocycloalkyl, the radicals
  • R b C0R c , R a NH 2 and TMS-N 3 are produced.
  • Formulas R b COR c and TMS-N 3 can be produced.
  • Compounds of formula (IX) can by reacting a
  • Compound of formula (I) can be prepared with H 2 S.
  • Compounds of formula (XI) can by reacting a
  • R a NH 2 are prepared.
  • the potassium salt of isocyanoacetic acid was prepared according to the method described in I. Hoppe, U. Schöllkopf, Chem. Ber. 1976, 109, 482-487.
  • Trityl resin (1-chloro-l, 1-diphenyl-l- (p-carboxyphenyl) - methane from aminomethyl polystyrene) (0.44 mmol / g)
  • this polymer sample was measured using FT-IR spectroscopy. It showed an isonitrile band at 2147 cm "1 .
  • benzylamine (1mmol) and 0.092ml isobutyraldehyde (1mmol) are in a mixture of MeOH / DCM abs. (2ml) precondensed for 1 hour. Then 500 mg of HMBA resin-bound ⁇ -dimethylamino- ⁇ -isocyanacrylic acid (0.25 mmol), 0.072 ml of thioacetic acid (1 mmol) and 2 ml of the above solvent mixture are added and shaken for 16 hours at room temperature. The resin is suctioned off and washed several times with DCM and MeOH. The resin is then dried in vacuo.
  • n-butylamine (1mmol) and 0.092ml isobutyraldehyde (1mmol) are in a mixture of MeOH / DCM abs. (2ml) precondensed for 1 hour. Then 500 mg of HMBA resin-bound ⁇ -dimethylamino- ⁇ -isocyanacrylic acid (0.25 mmol), 0.072 ml of thioacetic acid (1 mmol) and 2 ml of the above solvent mixture are added and shaken for 16 hours at room temperature. The resin is suctioned off and washed several times with DCM and MeOH. The resin is then dried in vacuo.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'isocyanure liés par polymères de formule générale (I), des procédés permettant de les préparer, ainsi que leur utilisation dans la synthèse d'hétérocycles et de bibliothèques de substances.
PCT/EP2002/014386 2001-12-18 2002-12-17 Isonitriles lies a la resine WO2003051795A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002358734A AU2002358734A1 (en) 2001-12-18 2002-12-17 Resin-bonded isonitriles

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2001162134 DE10162134A1 (de) 2001-12-18 2001-12-18 Harzgebundene Isonitrile
DE10162134.5 2001-12-18

Publications (2)

Publication Number Publication Date
WO2003051795A2 true WO2003051795A2 (fr) 2003-06-26
WO2003051795A3 WO2003051795A3 (fr) 2003-12-18

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PCT/EP2002/014386 WO2003051795A2 (fr) 2001-12-18 2002-12-17 Isonitriles lies a la resine

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AU (1) AU2002358734A1 (fr)
DE (1) DE10162134A1 (fr)
WO (1) WO2003051795A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005269A1 (fr) * 2002-07-09 2004-01-15 Morphochem Ag Komb Chemie Procede de production d'esters thiazol-2-ylmethyliques substitues
WO2005123140A2 (fr) * 2004-06-08 2005-12-29 Alza Corporation Preparation de conjugues macromoleculaires par reaction de condensation a quatre composants

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037983A1 (fr) * 1999-11-22 2001-05-31 Astrazeneca Ab Nouveaux reactifs polymeres fonctionnalises

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037983A1 (fr) * 1999-11-22 2001-05-31 Astrazeneca Ab Nouveaux reactifs polymeres fonctionnalises

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN J J ET AL: "Universal Rink-isonitrile resin: application for the traceless synthesis of 3-acylamino imidazo[1,2-aÜpyridines" TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, Bd. 42, Nr. 12, 18. März 2001 (2001-03-18), Seiten 2269-2271, XP004229899 ISSN: 0040-4039 *
SCH\LLKOPF, U ET AL: "Notiz }ber beta-dimethylamino-alpha-isocyanacryls{ure ester und ihre Verwendung in der Heterocyclenchemie" LIEBIGS ANNALEN DER CHEMIE., 1979, Seiten 1444-1446, XP002242440 VERLAG CHEMIE GMBH. WEINHEIM., DE ISSN: 0170-2041 in der Anmeldung erw{hnt *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005269A1 (fr) * 2002-07-09 2004-01-15 Morphochem Ag Komb Chemie Procede de production d'esters thiazol-2-ylmethyliques substitues
WO2005123140A2 (fr) * 2004-06-08 2005-12-29 Alza Corporation Preparation de conjugues macromoleculaires par reaction de condensation a quatre composants
WO2005123140A3 (fr) * 2004-06-08 2006-08-03 Alza Corp Preparation de conjugues macromoleculaires par reaction de condensation a quatre composants
US7476725B2 (en) 2004-06-08 2009-01-13 Alza Corporation Preparation of macromolecular conjugates by four-component condensation reaction

Also Published As

Publication number Publication date
AU2002358734A8 (en) 2003-06-30
DE10162134A1 (de) 2003-07-10
AU2002358734A1 (en) 2003-06-30
WO2003051795A3 (fr) 2003-12-18

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