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WO1999043662A1 - Synthese de 2-oxopiperazines sur support solide - Google Patents

Synthese de 2-oxopiperazines sur support solide Download PDF

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Publication number
WO1999043662A1
WO1999043662A1 PCT/US1999/002734 US9902734W WO9943662A1 WO 1999043662 A1 WO1999043662 A1 WO 1999043662A1 US 9902734 W US9902734 W US 9902734W WO 9943662 A1 WO9943662 A1 WO 9943662A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
hydrogen
resin
ester
Prior art date
Application number
PCT/US1999/002734
Other languages
English (en)
Inventor
Adam Golebiowski
Sean Rees Klopfenstein
Original Assignee
The Procter & Gamble Company
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 The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to CA002321302A priority Critical patent/CA2321302A1/fr
Priority to AU25939/99A priority patent/AU2593999A/en
Priority to EP99905883A priority patent/EP1056727A1/fr
Priority to IL13791899A priority patent/IL137918A0/xx
Priority to JP2000533419A priority patent/JP2002504545A/ja
Publication of WO1999043662A1 publication Critical patent/WO1999043662A1/fr
Priority to NO20004278A priority patent/NO20004278L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the subject invention relates to methods for synthesizing 2-oxopiperazine and homologous compounds, including libraries of such compounds, using a solid- support resin to facilitate purification of intermediates.
  • the subject invention also includes the above processes where the ⁇ -amino ester (V) is replaced by a ⁇ -amino ester (or other homologous ester) such that the final products are the homologous 7-member (or larger) ring compounds.
  • alkyl means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted.
  • alkyl may be used alone or as part of another word where it may be shortened to "alk” (e.g., in alkoxy, alkylacyl).
  • Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about six carbon atoms, more preferably still from one to about four carbon atoms; most preferred are methyl or ethyl.
  • Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about six carbon atoms.
  • Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings.
  • Preferred alkyl are unsaturated with from one to about three double or triple bonds; preferably they are mono- 3 unsaturated with one double bond; more preferred alkyl are saturated.
  • Preferred substituents of alkyl include alkyl, aryl, aryloxy, alkoxy, alkyl or aryl ester. More preferred alkyl are unsubstituted.
  • aryl means an aromatic hydrocarbon ring which is substituted or unsubstituted.
  • aryl may be used alone or as part of another word (e.g., in aryloxy, arylacyl).
  • Preferred aryl have from six to about ten carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms.
  • Preferred aryl is phenyl or naphthyl; most preferred is phenyl.
  • Preferred substituents of aryl include alkyl, aryl, alkoxy, aryloxy, alkyl or aryl ester, halo, nitro, amino, cyano, acyl, alkyl- or arylacyl. More preferred aryl are unsubstituted.
  • heteroatom means a nitrogen, oxygen, or sulfur atom.
  • heterocycle means a cyclic alkyl with one or more heteroatoms in the hydrocarbon ring(s).
  • Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms, most preferably one heteroatom.
  • Preferred heterocycles have from three to about ten carbon plus heteroatoms in the ring(s), more preferably from three to about seven; and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten.
  • Preferred heterocycles have one ring, but may have two, three, or more, fused rings. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl.
  • heteroaryl means an aromatic hydrocarbon ring with one or more heteroatoms in the ring(s).
  • Preferred heteroaryls have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms, most preferably one heteroatom.
  • Preferred heteroaryls have from five to about twelve carbon plus heteroatoms in the aromatic ring(s), more preferably from five to about nine; and a total of from five to about twenty carbon plus heteroatoms, more preferably from five to about ten.
  • Preferred heteroaryls have one ring, but may have two or more fused rings, at least one of which contains at least one ring heteroatom. Heteroaryls are unsubstituted or substituted. Preferred heteroaryl substituents are the same as for aryl.
  • the subject invention processes use solid-support resins capable of linking with the carboxy moiety of amino acids.
  • Preferred resins for use in the subject processes have hydroxymethylene linking moieties.
  • Particularly preferred are Merrifield or Wang resins such as polystyrene based resin Merrifield (100-200 mesh), 4
  • N-protected amino acids can be readily esterified to the above-mentioned resins.
  • resins are commercially available with N-protected amino acids already esterified to the resin (e. g. Boc-Gly-Merrifield resin catalog number 04-12-2507, available from Calbiochem-Novabiochem Corp., San Diego, California).
  • N-protecting groups on the above-mentioned amino acids are well known; they include t-butyloxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc); most preferred is Boc.
  • Boc t-butyloxycarbonyl
  • Fmoc 9-fluorenylmethoxycarbonyl
  • a subject invention process involves starting with a N-protected amino acid ester of a solid-support resin:
  • the N-protecting group is generally present on amino acid esters of resins because it is needed to properly esterify the amino acid onto the resin.
  • the subject process first requires removing this N-protecting group; this can be accomplished using any known method. (If the N-protecting group is not present, this procedure can be skipped.)
  • R can be any moiety that provides stable intermediates and final products for the subject processes.
  • Preferred R-* include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl acyl, alkyl or aryl ester, alkyl or aryl sulfonyl; more preferred R ⁇ include alkyl or aryl ester, alkyl or aryl sulfonyl.
  • reaction for providing R ⁇ in structure 8 examples include acetylation, sulfonylation, urea formation, reductive amination.
  • the next step of a subject invention process involves removing the N- protecting group from 8 by any known method (similar to the analogous procedure above).
  • Cleavage and cyclization is preferably achieved in a solution of acetic acid in 2-butanol.
  • the cleavage and cyclization reaction is not highly dependent on the amino acid or amino aldehyde used. There is substantial difference between six and seven member ring formation, the latter being cleaved and cyclized much slower.
  • the temperature required for substantially complete cleavage and cyclization is typically about 60-70°C.
  • Boc-glycine Merrifield resin ester (75 mg, 1.00 mM/g loading, 0.075 mM) is suspended in dichloromethane (DCM) for 5 min. The solvent is filtered off. 25% trifluoroacetic acid (TFA) / DCM is added and the mixture is shaken at room temperature for 1 hour to remove the Boc protecting group. After this time, the resin is filtered, washed with a 10% solution of diisopropylethylamine in DCM, and then a 1% solution of acetic acid in dimethylformamide (DMF).
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • the wet resin is suspended in a 1% solution of acetic acid in DMF and 4 eq (excess) of sodium cyanoborohydride (0.3 mM, 20 mg) is added to the 1% solution of acetic acid in DMF, followed by 2 eq of Boc-leucinal (0.15 mM, 32 mg). After 16-48 hours the reaction mixture is filtered, and the resin is washed with methanol, DMF and DCM. 25% TFA / DCM (ca. 5 mL) is added at room temperature and the resin is shaken for 1 hour to remove the Boc protecting group; then it is filtered and washed with DCM and methanol several times. A 2M solution of acetic acid in 2-butanol (ca. 10 mL) is added, and the reaction mixture is heated for 15 hours at 110°C, filtered and the resin washed three times with small amounts of DCM. Combined filtrates are evaporated and dried under vacuo to give crude product 5a (11.1 mg).
  • Examples 5b - 5e of the table below are synthesized in a similar manner as 5a. Cyclization cleavage of the compound 5e requires longer time (72 hours).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention se rapporte à des procédés servant à produire de la 2-oxopipérazine et des composés homologues, en utilisant une résine comme support solide, ce procédé consistant: (a) à éliminer le groupe protecteur de l'ester d'acide aminé N-protégé de la résine (le cas échéant), (b) à faire réagir l'ester de résine non protégé résultant avec un aldéhyde α-aminé N-protégé, (c) à modifier éventuellement l'intermédiaire résultant en substituant une fraction non hydrogène sur le résidu N de l'acide aminé, (d) à éliminer le groupe N-protecteur restant du résidu N de l'aldéhyde aminé, et (e) à effectuer le clivage/cyclisation du produit obtenu de la résine.
PCT/US1999/002734 1998-02-27 1999-02-08 Synthese de 2-oxopiperazines sur support solide WO1999043662A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002321302A CA2321302A1 (fr) 1998-02-27 1999-02-08 Synthese de 2-oxopiperazines sur support solide
AU25939/99A AU2593999A (en) 1998-02-27 1999-02-08 Solid support synthesis of 2-oxopiperazines
EP99905883A EP1056727A1 (fr) 1998-02-27 1999-02-08 Synthese de 2-oxopiperazines sur support solide
IL13791899A IL137918A0 (en) 1998-02-27 1999-02-08 Solid support synthesis of 2-oxopiperazines
JP2000533419A JP2002504545A (ja) 1998-02-27 1999-02-08 ２−オキソピペラジンの固体支持合成
NO20004278A NO20004278L (no) 1998-02-27 2000-08-25 Fremstilling av 2-oksopiperaziner pÕ en fast bærer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7613098P 1998-02-27 1998-02-27
US60/076,130 1998-02-27

Publications (1)

Publication Number Publication Date
WO1999043662A1 true WO1999043662A1 (fr) 1999-09-02

Family

ID=22130102

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/002734 WO1999043662A1 (fr) 1998-02-27 1999-02-08 Synthese de 2-oxopiperazines sur support solide

Country Status (7)

Country Link
EP (1) EP1056727A1 (fr)
JP (1) JP2002504545A (fr)
AU (1) AU2593999A (fr)
CA (1) CA2321302A1 (fr)
IL (1) IL137918A0 (fr)
NO (1) NO20004278L (fr)
WO (1) WO1999043662A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964181B2 (en) * 2006-03-30 2011-06-21 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs
AU2007233105B2 (en) * 2006-03-30 2013-05-16 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010222A1 (fr) * 1995-09-13 1997-03-20 Cortech, Inc. Procede de preparation de piperazines
WO1997048685A1 (fr) * 1996-06-18 1997-12-24 Glaxo Group Limited Inhibiteurs des metalloproteases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010222A1 (fr) * 1995-09-13 1997-03-20 Cortech, Inc. Procede de preparation de piperazines
WO1997048685A1 (fr) * 1996-06-18 1997-12-24 Glaxo Group Limited Inhibiteurs des metalloproteases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A.R. BATT ET AL.: "NOVEL CHOLECYSTOKININ RECEPTOR LIGANDS", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 4, no. 7, 1994, GB, pages 867 - 872, XP002103777 *
DAVID W. GORDON: "REDUCTIVE ALKYLATION ON A SOLID PHASE:SYNTHESIS OF A PIPERAZINEDIONE COMBINATORIAL LIBRARY", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 5, no. 1, 1995, GB, pages 47 - 50, XP000613027 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964181B2 (en) * 2006-03-30 2011-06-21 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs
AU2007233105B2 (en) * 2006-03-30 2013-05-16 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs

Also Published As

Publication number Publication date
NO20004278D0 (no) 2000-08-25
NO20004278L (no) 2000-08-25
CA2321302A1 (fr) 1999-09-02
EP1056727A1 (fr) 2000-12-06
IL137918A0 (en) 2001-10-31
JP2002504545A (ja) 2002-02-12
AU2593999A (en) 1999-09-15

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