WO2001016115A1 - Procede relatif a la synthese d'isoxazolidines - Google Patents

Procede relatif a la synthese d'isoxazolidines Download PDF

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Publication number
WO2001016115A1
WO2001016115A1 PCT/US2000/024149 US0024149W WO0116115A1 WO 2001016115 A1 WO2001016115 A1 WO 2001016115A1 US 0024149 W US0024149 W US 0024149W WO 0116115 A1 WO0116115 A1 WO 0116115A1
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alkyl
aryl
ethyl
formula
substituted
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PCT/US2000/024149
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English (en)
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Charles R. Johnson
Birong Zhang
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Chemrx Advanced Technologies, Inc.
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Priority to AU71058/00A priority Critical patent/AU7105800A/en
Publication of WO2001016115A1 publication Critical patent/WO2001016115A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings

Definitions

  • the present invention relates to a process for the synthesis of isoxazolidines.
  • This invention relates to synthesis of isoxazolidine based compounds.
  • United States Patent No. 5,153,193 discloses isoxazolidine compounds useful in treating memory dysfunctions characterized by a cholinergic effect such as Alzheimers disease. Isoxazolidine compounds are also known to have potential utility for the treatment of anxiety and for the improvement of learning disabilities.
  • isoxazolidine based compounds possess useful biological activity. Efforts continue to make a wider variety of compounds having a isoxazolidine nucleus. Current synthetic methods useful in making isoxazolidine derivatives are slow and time consuming. There is thus a need for a new process that will synthesize a plurality of isoxazolidine compounds in a short amount to time. Such an array or library of compounds can then be evaluated for its biological activity.
  • the present invention provides a process for synthesizing a compound or an array of Isoxazolidine based compounds of Formula I. Also provided by the present invention are novel compounds of formula-4 and a process to make the same. The compounds of formula-4 are useful in synthesizing isoxazolidine based compounds as described by the process of the present invention.
  • the present invention provides a process for synthesizing a compound or an array of compounds of Formula I .Formula I wherein
  • R 1 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from (CH 2 ) 0-6 aryl, (CH 2 )o- 6 substituted aryl, C ⁇ -C 4 alkyl, (CH 2 ) 0-6 heteroaryl and (CH 2 ) 0-6 heterocyclyl;
  • R 3 and R 4 independently at each occurance represent a group capable of forming a stable bond with the nitrogen atom to which they are attached; alternatively
  • R 3 and R 4 along with the nitrogen atom to which they are attached can form a heterocyclyl ring
  • R J is selected from H, COOR , 10 , CO-alkyl, CON(R 1 l 0 u )x 2 and CO-aryl ;
  • R 6 is selected from H, aryl, Cj. alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF 3 and (CH ) ⁇ -4 aryl;
  • R 10 independently at each occurance represents C 1-4 alkyl, aryl, H or heterocyclyl; said process comprising
  • R 1 , R 2 , R 5 and R 6 are defined above, and SS represents a solid support, to form a compound or an array of compounds of formula-4
  • R 1 , R 2 , R 5 , R 6 and SS are as defined above;
  • R 1 , R 2 , R 5 , R 6 and SS are as defined above, and ALKYL represents methyl, CH 2 -TMS or CH 2 -CN;
  • a preferred aspect of the present invention provides a process wherein R 1 is selected from H, C 1-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C 1-4 alkoxy, phenyl, C 1-4 alkyl and C 3-8 branched alkyl; heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from
  • R is selected from (CH 2 )i- 3 aryl
  • (CH 2 ) 1-3 substituted aryl said aryl substituted with one to five substituents selected from OC 1-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO 2 , C ⁇ -4 alkyl, phenyl, SC alkyl, NH 2 , NHC ⁇ -4 alkyl, N(C 1-4 alkyl) 2 and CF 3 ;
  • R 3 and R 4 are independently selected from H, C ⁇ _ 6 alkyl,
  • R 5 is selected from H, COOH, COC 2 H 5 , CO-aryl and COCH 3 ;
  • R 6 is selected from H, Ph, CH 3 , C 2 H 5 , aryl, CF 3 and benzyl.
  • a further preferred embodiment provides a process wherein step(i) is carried out in a suitable solvent selected from DMF, DMSO, toluene, DMA, THF, DCM and
  • step (iii) is carried out in the presence of a base selected from pyridine, triethyl amine, lutidine, trimethyl amine or excess of an amine of formula-6.
  • a base selected from pyridine, triethyl amine, lutidine, trimethyl amine or excess of an amine of formula-6.
  • step (i) is carried out in a suitable solvent selected from DMF,
  • DMSO and toluene at a temperature of from about 70°C to about 100°C.
  • Another aspect of the present invention provides an array of compounds of
  • R 1 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from (CH 2 ) 0-6 aryl, (CH 2 ) 0 . 6 substituted aryl, C ⁇ -C 4 alkyl, (CH 2 ) 0-6 heteroaryl and (CH 2 )o -6 heterocyclyl;
  • R 3 and R 4 independently at each occurance represent a group capable of forming a stable bond with the nitrogen atom to which they are attached; alternatively R 3 and R 4 along with the nitrogen atom to which they are attached can form a heterocyclyl ring;
  • R 5 is selected from H, COOR 10 , CO-alkyl, CON(R 10 ) 2 and CO-aryl ;
  • R 6 is selected from H, aryl, C 1-4 alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF 3 and (CH 2 ) 1- aryl; and R 10 independently at each occurance represents C 1-4 alkyl, aryl, H or heterocyclyl.
  • R 1 is selected from H, C ⁇ -6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C 1-4 alkoxy, phenyl, C 1- alkyl, C 3-8 branched alkyl and CN, heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from
  • R 2 is selected from
  • (CH 2 ) 1-3 substituted aryl said aryl substituted with one to five substituents selected from OC 1-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO 2 , C 1-4 alkyl, phenyl,
  • SC 1-4 alkyl NH 2 , NHd -4 alkyl, N(C 1-4 alkyl) 2 and CF 3 ;
  • R 3 and R 4 are independently selected from H, C 1-6 alkyl, l-(N,N-dimethyl)-prop-2-yl,
  • R 5 is selected from H, COOH, COC 2 H 5 , CO-aryl and COCH 3 ;
  • R 6 is selected from H, Ph, CH 3 , C 2 H 5 , aryl, CF 3 and benzyl.
  • R 1 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from (CH 2 ) 0 . 6 aryl, (CH 2 )o. 6 substituted aryl, C ⁇ -C 4 alkyl, (CH 2 ) 0- 6 heteroaryl and (CH 2 ) 0 - 6 heterocyclyl;
  • R 3 and R 4 independently at each occurance represent a group capable of forming a stable bond with the nitrogen atom to which they are attached; alternatively
  • R 3 and R 4 along with the nitrogen atom to which they are attached can form a heterocyclyl ring;
  • R 5 is selected from H, COOR 10 , CO-alkyl, CON(R 10 ) 2 and CO-aryl ;
  • R 6 is selected from H, aryl, C ⁇ -4 alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF 3 and (CH 2 ) 1-4 aryl;
  • R 10 independently at each occurance represents C ⁇ -4 alkyl, aryl, H or heterocyclyl
  • SS represents a solid support; said process comprising treating, in an a suitable solvent, a compound or an array of compounds of formula-2 .formula-2
  • R 1 , R 2 , R 5 and R 6 are defined above, and SS represents a solid support, to form a compound or an array of compounds of formula-4, where R 1 , R 2 , R , R and
  • R 1 is selected from H, C ⁇ -6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C ⁇ -4 alkoxy, phenyl, C ⁇ -4 alkyl, C 3-8 branched alkyl and CN, heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from
  • R is selected from (CH 2 ) 1-3 aryl, C 1-4 alkyl, (CH 2 ) 1-3 heteroaryl, and (CH 2 ) ⁇ . 3 substituted aryl, said aryl substituted with one to five substituents selected from OCj -3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO 2 , C ⁇ -4 alkyl, phenyl,
  • SC alkyl NH 2 , NHC 1-4 alkyl, N(C M alkyl) 2 and CF 3 ;
  • R 3 and R 4 are independently selected from H, C 1-6 alkyl, l-(N,N-dimethyl)-prop-2-yl,
  • R 5 is selected from H, COOH, COOCH 3 and COCH 3 ;
  • R 6 is selected from H, Ph, CH 3 , C 2 H 5 , aryl, CF 3 and benzyl.
  • a preferred embodiment provides a process for synthesizing compounds of formula-4 wherein step(i) is carried out in an inert medium selected from DMF, DMSO, toluene, DMA, THF, DCM and NMM, at a temperature of from about 40°C to about 120°C. In a further preferred process step (i) is carried out in an inert medium selected from DMF, DMSO and toluene, at a temperature of from about 70°C to about 100°C.
  • Another aspect of the present invention provides a compound or an array of compounds of formula-4
  • R 1 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
  • R is selected from (CH 2 )o- 6 aryl, (CH 2 ) 0-6 substituted aryl, C]-C 4 alkyl, (CH 2 )o -6 heteroaryl and (CH 2 ) 0-6 heterocyclyl;
  • R 5 is selected from H, COOR 10 , CO-alkyl, CON(R 10 ) 2 and CO-aryl ;
  • R 6 is selected from H, aryl, C ⁇ - alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF 3 and (CH 2 ) ⁇ -4 aryl;
  • R 10 independently at each occurance represents C ⁇ -4 alkyl, aryl, H or heterocyclyl
  • SS represents a solid support.
  • a compound of formula-2 (swelled with DMF) is mixed with a compound of formula-3. This mixture is heated at a temperature of from about 80°C to about 100°C for up to lh in a ventilated reaction vessel. This heated reaction mixture then is heated from about 15 h to about 72 h in a closed reaction vessel. The reaction mixture is cooled to ambient temperature, rinsed with DMF (x2) and DCM (x2). The rinsed reaction mixture is dried to yield a compound of formula-4.
  • STEP-2 formula-5
  • a compound of formula-4 from above is treated with a solution of a protonating agent, e.g., TFA, in an inert solvent, e.g., DCM, for about 1-5 minutes.
  • a protonating agent e.g., TFA
  • DCM inert solvent
  • the reaction solids are isolated and washed with DCM.
  • a alkylating agent e.g., TMS-diazomethane (2.0 M in hexanes) for up to about 15 minutes.
  • the reaction solids are isolated and washed with DCM (x 3-5). The solids are dried to yield a compound of formula-5.
  • STEP-3 Formula I: A compound of formula-5 is mixed in an inert solvent with a compound of formula-6, in the presence of a base, e.g., pyridine. The reaction mixture is agitated from about 12 to about 72 h at a temperature of from about 20° to about 50°C. The reaction mixture is filtered, the reaction solids are washed with a 1:9; MeOH:CH 2 Cl mixture (x2), the combined extracts are concentrated to yield a compound of Formula I.
  • a base e.g., pyridine
  • Compounds of formula-2 are prepared by treating sulfonamide based solid supports (or resins) with an ⁇ , ⁇ unsaturated acid in the presence of a coupling agent, catalyst (e.g., DIC) and a base (e.g., DMAP, DIPEA) in an inert medium, e.g., DCM.
  • a coupling agent e.g., DIC
  • a base e.g., DMAP, DIPEA
  • DCM inert medium
  • the reaction mixture is gently agitated for 12 to 36 h.
  • the reaction solids are sequentially washed with DCM (x2) and MeOH (x2). The washing sequence is repeated up to 4 times.
  • the washed solids are dried to yield a compound of formula-2.
  • nitrones are prepared using the procedure described by Confalone and Huie in Organic Reactions, Vol. 36, Chapter 1, John Wiley & Sons, which is incorporated herein by reference.
  • the procedure essentially comprises treating an aldehyde, e.g., glyoxylic acid monohydrate, with hydroxyl amine in DMF (solvent).
  • the reaction mixture is agitated from about 10 to about 20 minutes, filtered and the filtrate is concentrated to form the corresponding nitrone, e.g., compound of formula-3.
  • Alkylating Agents These agents are used in STEP-2 and are commercially available from sources like Aldrich Chemicals, Fluka and Lancaster.
  • cleaving amines are some times also referred to as cleaving amines. These compounds are primary or secondary amines which can be prepared by methods known to one skilled in the art. The primary and secondary amines of formula-6 also are available from commercial sources such as Aldrich Chemicals, Fluka and
  • the resin (compound of formula-1; 0.15 g) is placed in each well of a Polyfiltronics plate.
  • the resin is swelled with DMF.
  • the Polyfiltronics plate is placed in an open clamp with the wells open at the top and closed at the bottom.
  • a THF solution of a compound of formula-2 (nitrones, 1.0 mL; IM) is added to each well.
  • the Polyfiltronics plate is sealed from the top, placed on its side and shaken on a platform shaker from about 10 to about 30 minutes.
  • the Polyfiltronics plate then is placed horizontally.
  • the plates are vented and placed in an oven, preheated to about 95°C, for about 30 minutes or until gas evolution ceases.
  • the Polyfiltronic plate comprising wells containing a compound of formula-5, from above, is placed into an open clamp.
  • the bottom of the Polyfiltronics plate is sealed with a Teflon sheet.
  • a solution of an appropriate cleaving amine (formula-6; 0.4 M, 1.0 mL) in anhydrous pyridine is added to each row of wells of the Polyfiltronic plate.
  • the plate is sealed from the top and the contents of the plate wells agitated from about 12 to about 72 hours at ambient temperature.
  • the plate then is frozen in dry ice for about 30 minutes, undamped and placed on top of a 2 mL Beckman deepwell microtiter Beckman collection plate.
  • the polyfiltronics plate is thawed and the liquid contents of each well are drained into the collection plate.
  • the solid contents of each well are rinsed with a mixture of MeOH:CHCl 3 ; 1:9 (2 x 0.5 mL) and the elute is collected in the same Beckman collection plate.
  • the contents of each well from the Beckman collection plate are concentrated to yield a compound of Formula I.
  • the above synthesized compounds can be purified by using purification techniques known to one skilled in the art.
  • One such technique is the Supported Liquid-Liquid Extraction (SLE).
  • SLE Supported Liquid-Liquid Extraction
  • the SLE technique is especially useful in purifying compounds of Formula I, prepared in STEP-3 above.
  • the SLE process is influenced by the solubility characteristics of the cleaving amines (formula-6) used in STEP-3.
  • the SLE uses water as the wetting (activating) agent for the SLE material, for e.g., hydromatrix diatomaceous earth.
  • the SLE material for e.g., hydromatrix diatomaceous earth is wetted (activated) using 2 N HC1. Details of the SLE process are as described by Charles Johnson in Tetrahedron, 54 (1998) 4097-4106 which are incorporated herein by reference. Specific Examples: The following isoxazolidine compounds were prepared using the process of the present invention.
  • Mass spectra, 13 C NMR and 1H-NMR were obtained for compounds of Formula I synthesized using the process of the present invention. Mass spectra and 1H-NMR were obtained by conventional methods known to one skilled in the art. Elemental analysis was done using commercial services from Robertson Microlit Laboratories,
  • Suitable solvent is meant to indicate a solvent which is compatible with reaction conditions and able to swell the solid support (SS).
  • suitable solvent are THF, dioxane, toluene, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), dichloro methane (DCM), N-methyl pyrrolidinone (NMP) or mixtures thereof.
  • a list of suitable solvents can be found in Tet. Lett. 1998, 39, 8451-54, and is incorporated herein by reference.
  • Alkyl or “alkyl radical”, unless indicated otherwise, is meant to indicate a hydrocarbon moiety of up to 14 carbon atoms. This hydrocarbon is generally attached to at least one other atom, and can be straight chain, or branched, or cyclic.
  • aryl means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated.
  • a C 6 -C ⁇ 4 aryl group includes phenyl, naphthyl, anthracenyl, etc.
  • heteroaryl means aryl, as defined above, wherein one or more of the carbon atoms is replaced by a hetero atom chosen from N, O, and S.
  • the hetero atoms can exist in their chemically allowed oxidation states.
  • Sulfur (s) can exist as a sulfide, sulfoxide, or sulfone.
  • Each heteroaryl ring comprises from five (5) to fourteen (14) atoms.
  • heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, quinolyl, and pyrazinyl.
  • array of compounds indicates a collection of independent
  • library of compounds indicates a collection of individual compounds distinct from one another. Also included in the library of compounds is a mixture of the individual compounds.
  • heterocyclyl means a saturated or partially unsaturated cyclo alkyl group containing from 5 to 14 carbon atoms wherein one or more of the carbon atoms is replaced by a hetero atom chosen from N, O, and S.
  • the hetero atoms can exist in their chemically allowed oxidation states.
  • Sulfur (S) can exist as a sulfide, sulfoxide, or sulfone.
  • the heterocycloalkyl group can be completely saturated or partially unsaturated. Illustrative examples are piperidine, 1,4-dioxane, and morpholine.
  • group capable of forming a stable bond with a nitrogen atom represents a substituent which is capable of forming a covalent bond with a nitrogen atom to form a primary or secondary amine group to form a compound of formula-6.
  • substituents are optionally substituted alkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted alkoxy groups, l-(N,N-dimethyl)-prop-2-yl, 2-dimethylamino- 1 -methyl-ethyl, 3-pyrrolidin-l-yl-propyl, 2-morpholin-4-yl-ethyl, 2-(4-methyl- piperazin-l-yl)-ethyl, 4-diethylamino-l -methyl-butyl, 2-diethylamino-ethyl, 2- hydroxy-butyl, 3-methoxy-propyl, cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl, 2-amino benzyl, 2-fluoro benzyl, 2-oxo-azepan-3-yl, 2-(2-oxo- pyrrolidin-l-
  • substituted indicates that the group is substituted with one or more substituents selected from a group consisting of aryl, OCF 3 , halogen, S-haloalkyl, S- haloaryl, NHC 1-4 -CN, N(C 1-4 -CN) 2 , O-C(O)-C 1-4 alkyl, C 1-10 alkyl, nitro, thio-alkyl, cyano and C 1-4 alkoxy.
  • solid support signifies polymeric material for supported synthesis.
  • inert medium or “inert solvent” is intended to represent solvents which do not react with the reagents dissolved therein.
  • inert solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), dioxane, chloroform, and DMSO.
  • halogen represents Cl, I, Br or F.
  • base as used herein represents a tertiary amine. Illustrative examples are trialkyl amines, pyridine and lutidine.
  • protonating agent as used herein represents a chemical agent which is capable of donating a hydrogen (proton) atom to a hetero atom like nitrogen. Illustrative examples of protonating agents are trifluoro acetic acid (TFA), hydrochloric acid (HC1), p-toluene sulfonic acid and methane sulfonic acid.
  • DIPEA diisopropyl ethyl amine

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé relatif à la synthèse d'un composé ou d'une série de composés représentés par les formules (I) et (-4).
PCT/US2000/024149 1999-09-01 2000-08-31 Procede relatif a la synthese d'isoxazolidines WO2001016115A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
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WO2003014138A2 (fr) * 2001-08-03 2003-02-20 Jerini Ag Procede et dispositif d'immobilisation de composes
US7842815B2 (en) 2004-06-17 2010-11-30 Infinity Pharmaceuticals, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US7851637B2 (en) 2004-06-17 2010-12-14 Infinity Pharmaceuticals, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US7928244B2 (en) 2006-08-21 2011-04-19 Infinity Discovery, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners

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MINAKATA S ET AL: "Yb(OTf)3-Catalyzed 1,3-Dipolar Cycloaddition of Nitrone with Alkene;Switch in Diastereoselectivity by Solvent and Bidentate Auxiliary", TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 39, no. 29, 16 July 1998 (1998-07-16), pages 5205 - 5208, XP004162419, ISSN: 0040-4039 *
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003014138A2 (fr) * 2001-08-03 2003-02-20 Jerini Ag Procede et dispositif d'immobilisation de composes
WO2003014138A3 (fr) * 2001-08-03 2004-01-08 Jerini Ag Procede et dispositif d'immobilisation de composes
US7842815B2 (en) 2004-06-17 2010-11-30 Infinity Pharmaceuticals, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US7851637B2 (en) 2004-06-17 2010-12-14 Infinity Pharmaceuticals, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US8461191B2 (en) 2004-06-17 2013-06-11 Infinity Pharmaceuticals, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US7928244B2 (en) 2006-08-21 2011-04-19 Infinity Discovery, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US8178690B2 (en) 2006-08-21 2012-05-15 Infinity Pharmaceuticals, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
US8609706B2 (en) 2006-08-21 2013-12-17 Infinity Discovery, Inc. Compounds and methods for inhibiting the interaction of BCL proteins with binding partners

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