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WO2000012515A1 - Produits cycliques vinyle substitues de la reaction ene-yne - Google Patents

Produits cycliques vinyle substitues de la reaction ene-yne Download PDF

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Publication number
WO2000012515A1
WO2000012515A1 PCT/US1999/019622 US9919622W WO0012515A1 WO 2000012515 A1 WO2000012515 A1 WO 2000012515A1 US 9919622 W US9919622 W US 9919622W WO 0012515 A1 WO0012515 A1 WO 0012515A1
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WO
WIPO (PCT)
Prior art keywords
resin
scheme
reaction
compounds
ene
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.)
Ceased
Application number
PCT/US1999/019622
Other languages
English (en)
Inventor
Dirk A. Heerding
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to JP2000567537A priority Critical patent/JP2002523512A/ja
Priority to CA002341716A priority patent/CA2341716A1/fr
Priority to EP99942519A priority patent/EP1109816A4/fr
Publication of WO2000012515A1 publication Critical patent/WO2000012515A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • This invention relates to a novel intermediate for use in solid phase chemistry, its preparation and methods of use of the intermediate.
  • the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks.
  • the biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
  • an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
  • This invention relates to a novel resin-bound compound of formula (I).
  • Another aspect of the instant invention is in a method for making compounds using the resin-bound compound of formula (I) in solid phase synthesis.
  • This method is applicable to making combinatorial libraries of compounds designed around a core molecular structure using known methods of solid phase combinatorial chemistry or multiple simultaneous synthesis ("parallel synthesis").
  • the compounds or libraries of compounds made using this technology may be tested in biologically assays designed to test for a particular physical characteristic potentially useful in drug therapy.
  • solid support in the schemes
  • indensitrile resin polymeric resin
  • polymeric resin support polymeric resin support
  • POL polymeric resin support
  • the terms “resin,” “solid support,” “inert resin,” polymeric resin”, “polymeric resin support” or “POL” are used herein at all occurrences to mean a bead or other solid support such as beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, 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 a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface.
  • the solid support is suitably made of, for example, cross linked polystyrene resin, polyethylene glycol-polystyrene resin, and any other substance which may
  • resin-bound synthesis and “solid phase synthesis” are used herein interchangeably to mean a series of chemical reactions used to prepare either a single molecule/compound or a library of molecularly diverse compounds, wherein the chemical reactions are performed on a compound of formula (I). It will be understood that additional synthetic chemistry may be performed on the resin-bound compound of formula (I), and that the end products, which will be resin-bound, may be cleaved from the resin using trifluoroacetic acid..
  • Ene-yne 3 should be available from an allyl amine, a carboxylic acid, and an appropriately functionalized alkyne.
  • the solid phase chemistry was initiated by reacting the sodium anion of the allyl 4-hydroxybenzoate with chloro-Wang resin (Chloro-Wang resin was prepared from commercially available Wang resin (Polymer Labs; Lot No. WangOO ⁇ ; 250- 300 ⁇ M mesh; 1.7 meq/g loading) according to Raju, B.; Kogan, T.P. Tetrahedron Lett. 1997, 38, 4965-4968) in DMF to give 10. All of the reactions were characterized on solid phase using magic angle spinning ⁇ NMR (MAS NMR). (The identity and purity of the products were further established by cleaving an aliquot of the resin-bound material with 5% H 2 O in TFA.
  • MAS NMR magic angle spinning ⁇ NMR
  • the reaction sequence was used in a "split and mix" fashion to prepare a 10 x 4 x 5 x 16 membered isoindoline combinatorial library.
  • the R 1 component consisted of aryl or arylalkyl groups optionally substituted with halogen, alkyl and alkoxy groups.
  • the R 2 component consisted of hydrogen, alkyl or arylalkyl groups.
  • the R 3 component consisted of hydrogen or alkyl groups.
  • the dienophiles included cyclic, cis and trans disubstituted olefins containing at least one electron withdrawing group and alkynes containing at least one electron withdrawing group
  • reaction sequence can be used in conjunction with the IRORI Accu-TagTM system to provide a tagging method to identify the specific sequence experienced by any given bead.
  • This invention relates to compounds of formula (I):
  • Y is R-CO, R-SO2, R-PO2, wherein R is 4-hydroxyphenyl, 4-hydroxy-3- methoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3- hydroxy-4-methoxyphenyl, 3-hydroxyphenyl, 3-hydroxy-4-methylphenyl, 6- hydroxynapthyl, 4-hydroxyphenylmethyl, 4-hydroxyphenylethyl, can be prepared according to the teaching in copending patent application, Attorney Docket No. P50832P, USSN 60/098,532, filed August 31, 1998. See specifically, Schemes 1 and 2, and Examples 1 through 5.
  • Ph 3 P diethylazadicarboxylate
  • Cp 2 Ti(Cl)CH 2 Al(CH 3 ) 2
  • toluene reflux
  • the enolate of 5-Scheme 4 is prepared using a strong base, such as, lithium bis(trimethylsilyl)amide and is treated with a suitable l-mesyl-2-alkynyl moiety containing the R 2 substituent.
  • a 1-halo-, or l-tosyl-2-alkynyl moiety containing the R 2 substituent can also be employed.
  • An intramolecular ene-yne metathesis reaction using a suitable catalyst, such as, bis(tricyclohexylphosphine)benzylidene ruthenium dichloride furnishes the diene " U Scheme 4.
  • the carbamate 1 -Scheme 5 is deprotonated with a soluble base, such as, lithium tert-butoxide and is reacted with an allyl bromide containing the R 1 substituent, ' such as, 3-bromo-l-butene giving the subtituted carbamate 3; Scheme 5.
  • the protecting group is removed by conventional methods, such as, tetra-n-butylammonium fluoride.
  • the resulting amine is deprotonated with a soluble base, such as, lithium tert-butoxide and reacted with a l-methanesulfonyl-2-alkyne which contains the R 2 group.
  • a 1-halo-, or l-tosyl-2-alkynyl moiety containing the R 2 substituent can also be employed.
  • An intramolecular ene-yne metathesis reaction using a suitable catalyst, such as, bis(tricyclohexylphosphine)benzylidene ruthenium dichloride furnishes the diene 5-Scheme 5.
  • the hydroxyl group of 3-Scheme 6 is converted to a leaving group using conventional methods, such as, triphenyl phosphine and carbon tetrabromide and is then reacted with a 3- lithio-1-propene containing the R 2 substituent giving 4-Scheme 6.
  • An intramolecular ene-yne metathesis reaction using a suitable catalyst, such as, bis(tricyclohexylphosphine)benzylidene ruthenium dichloride furnishes the diene 5; Scheme 6.
  • the libraries may be prepared using the split and mix technique or parallel synthesis techniques.
  • the libraries generated from either of the the synthetic methods are molecularly diverse and are prepared simultaneously.
  • the steps of optionally dividing and recombining the resin-bound aryl silane intermediate into portions are for purposes of varying the derivatization on the resin-bound nucleophiles which are generated by the combinatorial synthesis.
  • the resin-bound nucleophile intermediates may be divided into portions at any point during the synthetic sequence. The portions may be recombined at any point during the sequence or, further iterations may be applied if more derivatization is required. Therefore, it will be obvious to the skilled artisan that the steps of dividing the portions, performing additional synthetic chemistry and recombining
  • portions may each be carried out more than once, depending upon the type of diversity required for the library of end-product compounds being prepared.
  • the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectrometry or mass spectrometry.
  • the compounds may be characterized while remaining resin-bound or they can be cleaved from the resin using the conditions described above, and then analyzed.
  • a partial array of compound members of the library may be cleaved from the resin, characterized and analyzed, while leaving a partial array of the compound members of the library bound to the resin.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne un nouveau produit intermédiaire s'utilisant en chimie en phase solide, sa préparation et des procédés d'utilisation de ce produit intermédiaire.
PCT/US1999/019622 1998-08-31 1999-08-26 Produits cycliques vinyle substitues de la reaction ene-yne Ceased WO2000012515A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000567537A JP2002523512A (ja) 1998-08-31 1999-08-26 エン−イン反応によるビニル置換環状生成物
CA002341716A CA2341716A1 (fr) 1998-08-31 1999-08-26 Produits cycliques vinyle substitues de la reaction ene-yne
EP99942519A EP1109816A4 (fr) 1998-08-31 1999-08-26 Produits cycliques vinyle substitues de la reaction ene-yne

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9852998P 1998-08-31 1998-08-31
US60/098,529 1998-08-31

Publications (1)

Publication Number Publication Date
WO2000012515A1 true WO2000012515A1 (fr) 2000-03-09

Family

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Application Number Title Priority Date Filing Date
PCT/US1999/019622 Ceased WO2000012515A1 (fr) 1998-08-31 1999-08-26 Produits cycliques vinyle substitues de la reaction ene-yne

Country Status (4)

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EP (1) EP1109816A4 (fr)
JP (1) JP2002523512A (fr)
CA (1) CA2341716A1 (fr)
WO (1) WO2000012515A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6787635B2 (en) * 2001-04-05 2004-09-07 3M Innovative Properties Company Solid phase synthesis supports and methods

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939268A (en) * 1994-07-26 1999-08-17 The Scripps Research Institute Combinatorial libraries of molecules and methods for producing same

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
FARINA ET AL.: "Large Rate Accelerations in the Stille Reaction with Tri-2-furylphosphine and Triphenylarsine as Palladium Ligands: Mechanistic ans Synthetic Implications.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 113, no. 2, 1991, pages 9585 - 9595, XP002923480 *
FINKELSTEIN ET AL.: "A Diels-Alder Route to 7,8-Disubstituted-1,2,3,4-Tetrahydroisoquinolines.", TETRAHEDRON LETTERS, vol. 21, 1980, pages 3323 - 3326, XP002923483 *
KANEMASA ET AL.: "DOUBLE DIELS-ALDER REACTION OF TRANS-3-METHYLENE-1,4-HEXADIENE AND 1-METHYL-3- METHYLENE-4 PENTENYL TOSYLATE.", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 59, no. 6, 1986, pages 1869 - 1876, XP002923482 *
KINOSHITA ET AL.: "Ruthenium Catalyzed Enyne Metathesis", SYNLETT, vol. 12, December 1994 (1994-12-01), pages 1020 - 1022, XP002923478 *
NARASAKA ET AL.: "Rearrangement of Allylic and Propargylic Alcohols Catalyzed by the Combined Us of Tetrabutylammonium Perrhenate (VII) and p-Toluenesulphonic Acid.", CHEMISTRY LETTERS, vol. 8, 1 October 1991 (1991-10-01), pages 1413 - 1416, XP002923481 *
NARASAKA ET AL.: "Rearrangement of Allylic and Propargylic Alcohols Catalyzed by the Combined Use of Tetrabutylammonium Perrhenate (VII) and p-Toulenesulfonic Acid.", TETRAHEDRON, vol. 48, no. 11, 1992, pages 2059 - 2068, XP002923479 *
See also references of EP1109816A4 *

Also Published As

Publication number Publication date
EP1109816A1 (fr) 2001-06-27
CA2341716A1 (fr) 2000-03-09
JP2002523512A (ja) 2002-07-30
EP1109816A4 (fr) 2004-12-15

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