WO2002020493A2 - Synthese en phase solide de 2-imidazolones exemptes de substances a l'etat de traces - Google Patents

Synthese en phase solide de 2-imidazolones exemptes de substances a l'etat de traces Download PDF

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Publication number
WO2002020493A2
WO2002020493A2 PCT/US2001/027207 US0127207W WO0220493A2 WO 2002020493 A2 WO2002020493 A2 WO 2002020493A2 US 0127207 W US0127207 W US 0127207W WO 0220493 A2 WO0220493 A2 WO 0220493A2
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Prior art keywords
polymer
bound
acetal
formula
haloacetaldehyde
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PCT/US2001/027207
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WO2002020493A3 (fr
Inventor
Jie Fei Cheng
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Priority to AU2001288605A priority Critical patent/AU2001288605A1/en
Publication of WO2002020493A2 publication Critical patent/WO2002020493A2/fr
Publication of WO2002020493A3 publication Critical patent/WO2002020493A3/fr
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    • 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
    • C07D233/70—One oxygen atom
    • 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

  • This invention relates to a novel process for preparing 2-imidazolones compounds.
  • This invention also relates to novel polymer-bound halo- and amino- acetaldehyde acetal compounds.
  • This invention also relates to a novel process for preparing polymer-bound halo- and amino-acetaldehyde acetal compounds.
  • BACKGROUND 2-lmidazolone derivatives have long been known to possess interesting biological activities. Examples include herbicial agents (R. W. Luckenbaugh, US 3,216,816), antifungal agents (Itoh, K. et al., EP 884,311 ), anti-coagulants (Mohan, R.
  • this invention provides a process for preparing a 2- imidazolone compound of the formula (I)
  • said acid in the step 4) is trifluoroacetic acid or hydrochloric acid.
  • this invention also provides a polymer-bound haloacetaldehyde acetal compound of formula (IV), wherein x is chloro, bromo or iodo.
  • this invention also provides a process for preparing a polymer-bound haloacetaldehyde acetal compound of formula (IV) by reacting a haloacetaldehyde diethyl acetal (III) with a polymer-bound 1 ,2-ethylenediol under acidic conditions, wherein x is chloro, bromo or iodo.
  • this invention also provides a polymer-bound aminoacetaldehyde acetal compound of formula (V), wherein Ri represents hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl groups.
  • this invention also provides a process for preparing a polymer-bound aminoacetaldehyde acetal compound of formula (V) by reacting a polymer-bound haloacetaldehyde acetal (IV) with a primary amine of the formula
  • R ⁇ NH 2 wherein Ri represents hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl groups.
  • reaction of a haloacetaldehyde diethyl acetal with a polymer-bound 1 ,2-ethylenediol affords the polymer-bound haloacetaldehyde acetal (IV).
  • the acids that make acidic conditions in this reaction include but not limited to p-toluenesulfonic acid, camphor sulfonic acid, hydrochloric acid and Lewis acids.
  • the preferred acid is camphor sulfonic acid.
  • the polymer-bound 1 ,2-ethylenediol is purchased from commercial sources
  • a polymer-bound glycerol may be prepared from a polymer through derivatization.
  • a polymer-bound glycerol can be prepared from a polymer and a glycerol derivative (Lenzoff, C.C. et al., Can. J. Chem. 51 ,
  • Reaction of a polymer-bound haloacetaldehyde acetal (IV) with a primary amine of the formula R 1 NH 2 in a solvent forms a polymer-bound aminoacetaldehyde acetal (V).
  • solvent used for this reaction step, except that the amine RiNH 2 be at least somewhat soluble therein.
  • most organic solvents such as DMSO, DMF or toluene can be utilized successfully for the reaction.
  • DMSO is the preferred solvent.
  • the reaction is conducted at the elevated temperature, for example, at 80°C.
  • Reaction of a polymer-bound aminoacetaldehyde acetal (V) with isocyanates of the formula R 2 NCO gives a urea acetaldehyde acetal intermediate (VI) under a variety of conditions.
  • the reaction goes smoothly in solvents such as THF, CH 2 CI 2 or toluene.
  • the reaction can be conducted in the presence or absence of bases.
  • the reaction was preferably conducted at 60°C in toluene in the presence of DMAP or DIPEA.
  • This process described in the invention could be useful for making a large number of compounds for, but not limited to, high-throughput screening.
  • One of the potential advantages of this reaction is that it yields a reusable polymer along with the product.
  • This invention also provides a polymer-bound haloacetaldehyde acetal compound of formula (IV), wherein x is chloro, bromo or iodo, which may be prepared by the process described throughout this specification.
  • This polymer- bound haloacetaldehyde is a useful intermediate in preparing compounds with aldehyde functionalities or the like.
  • This invention also provides a polymer-bound aminoacetaldehyde acetal compound of formula (V), wherein Ri represents hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl groups, which is a useful intermediate in preparing compounds with aldehyde and/or amino functionalities.
  • Acid means an acid that facilitates acetal hydrolysis. It includes organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, acetic acid, formic acid or inorganic acids such as hydrohalic acids.
  • organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, acetic acid, formic acid or inorganic acids such as hydrohalic acids.
  • the preferred acid in the invention for the cleavage (hydrolysis) of acetal functionality from the solid support is trifluoroacetic acid or hydrochloric acid.
  • Acid labile linkage means the link between an organic molecule and a solid support (or polymer, resin) can be removed or cleaved by treatment with an acid while remaining stable to other reagents.
  • acid labile linkage include ether or ester bond on Wang resin (Wang, S.-S. J. Am. Chem. Soc. 95, 1328 (1973)), amide bond on Rink resin (Rink, H., Tetrahedron Lett. 28, 3787 (1987)), or acetal on the polymer as described in the invention.
  • Preferred acids to cleave the product from these polymers (resins) are trifluoroacetic acid (TFA) or HF.
  • Alkyl as used herein, means a cyclic, branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, cyano, nitro, hydroxyl, mercapto, carboxy, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents e.g., halogen, alkoxy, acyloxy, amino, cyano, nitro, hydroxyl, mercapto, carboxy, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • Aryl as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can be optionally unsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
  • Halo as used herein, means chloro, bromo or iodo atoms in the invention.
  • the fluorine atom is excluded in the invention.
  • Heteroaryl as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., pyrridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) and having at least one hetero atom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, halo, mercapto, and other substituents.
  • Heterocyclyl as used herein, means radical heterocycles which are saturated, or unsaturated and non-aromatic.
  • heterocycles are of 5 or 6 members.
  • the heteroatom(s) are from one to three Ns, and wherein when the heterocycle is five membered and non-aromatic, preferably it has one or two heteroatoms selected from O, N, or S.
  • Polymer-bound 1 ,2-ethylenediol as used herein, means that 1 ,2-dihydroxyl ethane unit is linked through an ethylene carbon to a polymer via any stable linkage.
  • protecting group means a chemical group that exhibits the following characteristics: (I) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) generated in such protected reactions. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2 nd Ed. John Wiley & Sons, (1991 ).
  • Solid-phase synthesis means a heterogeneous reaction in which one of reactants is covalently connected to a solid support (polymer or resin, etc.). Other reactants are dissolved in an organic solvent or solvents and the product is obtained through a cleavage step from the solid support.
  • Solid support means a substrate which is inert to the reagents and reaction conditions described herein, as well as being substantially insoluble in the media used.
  • Representative solid supports include inorganic substrates such as kieselguhr, silica gel, and controlled pore glass; organic polymers including polystyrene, polypropylene, polyethylene glycol, polyacrylamide, cellulose, and the like; and composite inorganic/polymeric compositions such as polyacrylamide supported within a matrix of kieselguhr particles. See J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, IL, 1984). A polymer is preferably used in this invention.
  • solid support includes polymeric supports such as the polyethylene glycol supports described by Janda et al., Proc. Natl. Acad. Sci. USA, 92, 6419-6423 (1995) and S. Brenner, WO 95/16918, which are soluble in many solvents but can be precipitated
  • the solid support is designated as ⁇ - ⁇ in this specification.
  • solvent means a liquid that can dissolve another compound and has no adverse effect on the reaction or on the reagents involved.
  • suitable solvents include alcohols (methanol, 1 -butanol, phenol, trifluoroethanol, hexafluoro-2-propanol, etc.), hydrocarbons (benzene, toluene, etc.), amides (dimethyl acetamide, dimethylformamide, etc.), halides (dichloromethane, dichloroethane, etc.), and ethers (tetrahydrofuran, dioxane, etc.).
  • Other solvents include water, 1 -methyl-2-pyrrol ⁇ dine, diethyl phosphite, tetramethaylsulphone, dimethyl sulphoxide, acetonitrile and pyridine.
  • Raceies solid-phase synthesis means that a solid-phase synthesis that leaves no trace of the linker used for tethering the starting building blocks to the solid support.
  • Under acidic conditions means the acetal formation reaction is conducted in the presence of an acid which itself is not part of the reactant.
  • the acid can be either inorganic acids such as hydrochloric acid, sulfuric acid or Lewis acids or organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, camphor sulfonic acid. Preferred acids are camphor sulfonic acid or any Lewis acids.
  • CDCI 3 deutered chloroform
  • DIPEA diisopropylethyl amine
  • MgSO magnesium sulfate
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography The following alkyl group abbreviations are used.
  • H nuclear magnetic resonance spectra is measured in CDCI 3 or other solvents as indicated by a Varian NMR spectrometer (Unity Plus 400, 400 MHz for 1 H) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane.
  • the peak shapes are denoted as follows, s, singlet; d, doublet; t, triplet; m, multiplet.
  • the polymer that used in the reaction is a commercially available polymer- bound glycerol (II).
  • Acetal exchange of a haloacetaldehyde diethyl acetal such as bromoacetaldehyde diethyl acetal with the polymer-bound glycerol affords the polymer-bound haloacetaldehyde acetal (IV) in the presence of camphor sulfonic acid in CH2CI 2 at room temperature.
  • the formation of the halide on the solid support is confirmed by infrared spectrometric analysis and weight change of the resin.
  • CSA (1 eq.) was added followed by 2-bromoacetaldehyde diethyl acetal (10 eq) to the suspension of polymer-bound glycerol (250 mg, 1.38 mmol/g, Aldrich) in CH 2 CI 2 (3 mL) in a 10 mL tube with frit and screw cap.
  • the suspension was shaken in a shaker at room temperature for 12 h.
  • the solvent was drained, and the polymer was washed with DMF (3 x 6 mL), MeOH (3 x 6 mL) and CH 2 CI 2 (3 x 6 mL) and dried under vacuum at room temperature.

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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)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

Cette invention a trait à la synthèse en phase solide de 2-imidazolones exemptes de substances à l'état de traces. On fait réagir un haloacétaldéhyde acétal à liaison polymère, préparé par un échange d'acétal de haloacétaldéhyde diéthyl acétal avec un 1,2-éthylènediol à liaison polymère, avec une amine primaire correspondant à la formule R1NH2 afin d'obtenir un haloacétaldéhyde acétal à liaison polymère. On fait réagir ce dernier avec un isocyanate correspondant à la formule R2NCO afin d'obtenir l'intermédiaire urée acétal à liaison polymère correspondant, lequel, une fois traité au moyen d'un acide, donne les composés de 2-imidazolone.
PCT/US2001/027207 2000-09-06 2001-08-31 Synthese en phase solide de 2-imidazolones exemptes de substances a l'etat de traces Ceased WO2002020493A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001288605A AU2001288605A1 (en) 2000-09-06 2001-08-31 A traceless solid-phase synthesis of 2-imidazolones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23032300P 2000-09-06 2000-09-06
US60/230,323 2000-09-06

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WO2002020493A2 true WO2002020493A2 (fr) 2002-03-14
WO2002020493A3 WO2002020493A3 (fr) 2002-10-31

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046758A3 (fr) * 2006-10-19 2009-06-11 Hoffmann La Roche Dérivés d'imidazolone et d'imidazolidinone utilisés en tant qu'inhibiteurs de l'enzyme 11b-hsd1 pour le diabète
US8263635B2 (en) 2009-06-26 2012-09-11 Novartis Ag Inhibitors of CYP 17
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2707186A (en) * 1954-05-06 1955-04-26 Hoffmann La Roche Imidazolone derivatives
US3216816A (en) * 1960-10-13 1965-11-09 Du Pont Herbicidal composition and method
US3355457A (en) * 1965-05-21 1967-11-28 American Cyanamid Co Substituted 2-imidazolinones
AR021509A1 (es) * 1998-12-08 2002-07-24 Lundbeck & Co As H Derivados de benzofurano, su preparacion y uso

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046758A3 (fr) * 2006-10-19 2009-06-11 Hoffmann La Roche Dérivés d'imidazolone et d'imidazolidinone utilisés en tant qu'inhibiteurs de l'enzyme 11b-hsd1 pour le diabète
JP2010506876A (ja) * 2006-10-19 2010-03-04 エフ．ホフマン−ラ ロシュ アーゲー 糖尿病のための１１β−ＨＳＤ１阻害剤としてのイミダゾロン及びイミダゾリジノン誘導体
EP2308851A1 (fr) * 2006-10-19 2011-04-13 F. Hoffmann-La Roche AG Dérivés d'imidazoline et d'imidazolidinone en tant qu'inhibiteurs de 11B-HSD1 pour le traitment du diabètes
RU2439062C2 (ru) * 2006-10-19 2012-01-10 Ф.Хоффманн-Ля Рош Аг Производные имидазолона и имидазолидинона как 11в-hsd1 ингибиторы при диабете
US8129423B2 (en) 2006-10-19 2012-03-06 Hoffman-La Roche Inc. Imidazolone and imidazoloidinone derivatives as 11b-HSD1 inhibitors
US8263635B2 (en) 2009-06-26 2012-09-11 Novartis Ag Inhibitors of CYP 17
USRE45173E1 (en) 2009-06-26 2014-09-30 Novartis Ag Inhibitors of CYP 17
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
US9339501B2 (en) 2011-04-28 2016-05-17 Novartis Ag 17a-hydroxylase/C17,20-lyase inhibitors

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WO2002020493A3 (fr) 2002-10-31

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