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WO2001016116A1 - Procedes relatifs a la synthese d'isoxazolines et d'isoxazoles - Google Patents

Procedes relatifs a la synthese d'isoxazolines et d'isoxazoles Download PDF

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Publication number
WO2001016116A1
WO2001016116A1 PCT/US2000/024148 US0024148W WO0116116A1 WO 2001016116 A1 WO2001016116 A1 WO 2001016116A1 US 0024148 W US0024148 W US 0024148W WO 0116116 A1 WO0116116 A1 WO 0116116A1
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Prior art keywords
alkyl
formula
substituted
aryl
heterocyclyl
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PCT/US2000/024148
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English (en)
Inventor
Charles R. Johnson
Birong Zhang
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ChemRx Advanced Technologies Inc
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ChemRx Advanced Technologies Inc
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Priority to AU71057/00A priority Critical patent/AU7105700A/en
Publication of WO2001016116A1 publication Critical patent/WO2001016116A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • 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
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Definitions

  • This invention relates to a process for the synthesis of isoxazolines and isoxazoles.
  • This invention relates to a process to synthesize isoxazoline and isoxazole based compounds.
  • Small molecule isoxazoline compounds are being studied as potential GP Ilb/IIIa receptor agonists, in the treatment of thrombosis, cerebrovascular ischemia and cardiovascular diseases.
  • Novel substituted isoxazole-3-carboxylate amide derivatives are being studied for their ability to inhibit gastric secretion and to be useful for the treatment of peptic ulcers.
  • Isoxazole compounds are also reported to be chymase inhibitors, thereby being useful in the treatment of hypertension and other cardiovascular disorders.
  • isoxazoline and izoxazole based compounds possess useful biological activity. Efforts continue to make a wider variety of compounds having a isoxazoline or isoxazole nucleus. Current synthetic methods useful in making these derivatives are slow and time consuming. There is thus a need for a new process that will synthesize a compound or an array of isoxazoline and isoxazole based compounds in a short amount to time. Such individual compounds or the array or library of compounds can then be evaluated for their biological activity.
  • the present invention provides a process for synthesizing a compound or an array of isoxazoline based compounds of
  • Formula I Also provided by the present invention is a process for synthesizing a compound or an array of isoxazole based compounds of Formula II.
  • the present invention also provides an array of compounds of Formula I and Formula II respectively.
  • the present invention provides a process for synthesizing a compound or an array of compounds of Formula I
  • 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, -Cg alkyl, (CH 2 )o -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 optionally substituted with NH-C(O)C ⁇ . 4 alkyl or NH-C(O)O-C ⁇ -6 alkyl; said process comprising
  • R 3 and R 4 are as defined above.
  • a preferred embodiment provides a process wherein
  • R 1 represents H, C ⁇ -6 alkyl, Ph or 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 ) ⁇ -3 aryl
  • (CH ) ⁇ -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 M alkyl, phenyl, SC M alkyl, NH 2 ,
  • NHC ⁇ - alkyl N(C 1-4 alkyl) 2 and CF 3 ;
  • R 3 and R 4 are independently selected from H, C ⁇ -6 alkyl, l-(N,N-dimethyl)-prop-2-yl,
  • step (i) is a tertiary amine.
  • a further preferred process provides a process wherein the base in step (i) is NMM, triethyl amine, DIPEA or a mixture thereof; the reaction temperature in step (i) ranges from about 40°C to about 100°C; and wherein the aprotic solvent in step (ii) is selected from pyridine, THF and dioxane.
  • Another aspect of the present invention provides a process to synthesize a compound or an array of compounds of Formula LT
  • R 1 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
  • R R 22 iiss sseelleecctteedd ffrroomm ((CCHH 22 )) 00--66 aarryyll,, ((CCH 2 )o -6 substituted aryl, C ⁇ -C 8 alkyl, (CH 2 )o -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 optionally substituted with NH-C(O)C 1-4 alkyl or NH-C(O)O-C 1-6 alkyl; said process comprising: treating, in an inert solvent, a compound of Formula I
  • a preferred embodiment of this aspect of the invention provides a process wherein the base is selected from DBU, tetramethyl guanidine, the reaction temperature ranges from about 40°C to about 75°C, and wherein one of R 3 and R 4 represents H.
  • the present invention in one of its aspects, also provides an array of compounds of Formula I and Formula II respectively.
  • a compound of formula-1 (100 mg; 0.11 mmol) is mixed with a compound of formula-2 (1 mL; 0.5 mmol) and a base, e.g. NMM, (0.5 mmol). This mixture is agitated for about 30 minutes at ambient temperature. This mixture then is agitated at a temperature of from about 20°C to about 100°C from about 12 h to about 72 h. The mixture is cooled to ambient temperature and the reaction solids are sequentially washed with DMF (x3) and DCM (x3). The washing sequence is repeated up to three times. The washed reaction mixture is dried to yield a compound of formula-3.
  • a base e.g. NMM
  • STEP-2 Formula I A compound of formula-3 (1 eq.) is combined with a mixture of a compound of formula-4 (2-5 eq.) and a suitable solvent, preferably in the presence of an agent capable of accepting a proton, e.g., pyridine or an excess of a compound of formula-4.
  • an agent capable of accepting a proton e.g., pyridine or an excess of a compound of formula-4.
  • the resulting mixture is agitated at a temperature of from about 20°C to about 40°C, from about 12 to about 36 h.
  • the reaction mixture is filtered, and the reaction solids are washed in succession with MeOH (xl), 10% MeOH in CHC1 3 (xl) and MeOH (xl).
  • a compound of Formula I is combined with an inert solvent, e.g., 1,2- dichloroethane to form a mixture.
  • This mixture is heated at a temperature of from about 40°C to about 60°C to form a solution.
  • This resulting solution then is combined with a base, e.g., DBU, (0.4 mL) and an oxidizing agent, e.g.,BrCCl 3 (0.4 mmol).
  • the resulting mixture then is agitated from about 8 h to about 36 h at a temperature of from about 40°C to about 60°C.
  • the reaction mixture is washed in succession with an acid , e.g., dil. HC1, and brine.
  • the organic layer is dried (MgSO 4 ) and evaporated to yield a compound of Formula II.
  • the resin (compound of formula-1; 0.10 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 DMF solution of a compound of formula-2 (a halo oxime, 1.0 mL; 1M) and a base, e.g., NMM (0.5 mmol per well) are 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. These plates then are heated from about 40°C to about 60°C for about 12 to about 72 hours.
  • the plates are cooled to ambient temperature and the resin from each well is sequentially rinsed with DMF (x3) and DCM (x3).
  • the rinsing sequence is repeated up to 3 times to yield a compound of formula-3.
  • STEP-2 Formula I
  • the Polyfiltronic plate comprising wells containing a compound of formula-3, 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-4; 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.
  • a compound of Formula I (0.1 mmol) is placed in each well of a deep well microtiter plate, e.g., MultiChem from Polyfiltronics. Contents of each well are combined with anhydrous 1,2-dichloroethane (about 1 mL per well). The plate is sealed from the top and the contents of the plate wells are heated at a temperature of from about 40°C to about 60°C to form a homogenous mixture. The homogenous contents of the plate wells then are agitated at ambient temperature for about 30 minutes. These contents are diluted with DBU (0.4 mmol) and BrCCl 3 (0.4 mmol).
  • the plate is sealed from the top and the well contents are heated, with gentle agitation, at a temperature of from about 40°C to about 60°C for about 12 h to about 36 h.
  • the contents of each well are treated in succession with an acidic solution, e.g., dil. HCl and brine.
  • the organic layer is dried (MgSO 4 ) and evaporated to yield a compound of Formula II.
  • Compounds of formula-1 are prepared by coupling a thiophenol resin (1 eq.; Aldrich Chemicals) with an ⁇ , ⁇ unsaturated acid (2-4 eq.).
  • the coupling process comprises combining an ⁇ , ⁇ unsaturated acid ( 3 eq. wrt the thiophenol resin), a coupling agent (e.g., DIC, 3 eq. wrt the thiophenol resin) and DCM (about 6 mL per gram of the thiophenol resin). This mixture is agitated for about 10 minutes.
  • the agitated mixture then is combined with a thiophenol resin 91 eq.), a catalyst (e.g., DMAP; 0.1 to 0.5 eq.
  • the resulting reaction mixture is agitated from about 12 to about 48 h.
  • the reaction solids are sequentially washed with DCM (x4), MeOH (x20), DCM (x4) and MeOH (xl). The washing sequence is repeated up to 4 times.
  • the washed solids are dried and tested for the presence of a phenol using the FeC13/pyridine test for detecting phenols. This test is described by Popebucher et. al.
  • halo oximes are prepared by treating an oxime with a halogenating agent such as chlorine sodium hypochloride, NBS or NCS.
  • a halogenating agent such as chlorine sodium hypochloride, NBS or NCS.
  • the process essentially comprises treating an oxime in DMF (solvent) with a halogenating agent.
  • the resulting oxime solution is agitated from about 30 minutes to about 3 h to form the corresponding halo oxime (formula-2).
  • These halo oximes then can be used in the solution form in STEP-1.
  • 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 and Formula II, prepared above. 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 isoxazoline compounds were prepared using the process of the present invention. Standard A:
  • Mass spectra, 13 C NMR and ' H-NMR were obtained for compounds of Formula I synthesized using the process of the present invention. Mass spectra and ' H-NMR were obtained by conventional methods known to one skilled in the art. Elemental analysis was done using commercial services from Robertson Microlit Laboratories, Inc.
  • 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 (individual) compounds that are synthesized by the process of the present invention.
  • 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-4.
  • 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 0 alkyl, nitro, thio-alkyl, cyano, O-aryl, C 1-3 alkylenyl-aryl and C 1- alkoxy.
  • 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 0 alkyl, nitro, thio-alkyl, cyano, O-aryl, C 1-3 alkylenyl-aryl and C 1- 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), 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 (HCl), p-toluene sulfonic acid and methane sulfonic acid.
  • TFA trifluoro acetic acid
  • HCl hydrochloric acid
  • p-toluene sulfonic acid and methane sulfonic acid.
  • DIPEA diisopropyl ethyl amine
  • NBS N-bromo succinimide
  • NMM N-methyl morpholine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés relatifs à la synthèse d'un composé ou d'une série de composés représentés par les formules (I) et (II), respectivement. L'invention concerne également une série de composés représentés par les formules (I) et (II), respectivement.
PCT/US2000/024148 1999-09-01 2000-08-31 Procedes relatifs a la synthese d'isoxazolines et d'isoxazoles Ceased WO2001016116A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU71057/00A AU7105700A (en) 1999-09-01 2000-08-31 Process for synthesizing isoxazolines and isoxazoles

Applications Claiming Priority (2)

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US15196299P 1999-09-01 1999-09-01
US60/151,962 1999-09-01

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WO2001016116A1 true WO2001016116A1 (fr) 2001-03-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080604A1 (fr) * 2002-03-21 2003-10-02 Glaxo Group Limited Composes de tetrahydrofuran de dihydroisoxazolyle substitues utilises en tant qu'intermediaire dans la preparation de derives de 2-(purine-9-yl) - tetrahydrofuran
JP2007537286A (ja) * 2004-05-14 2007-12-20 アイアールエム・リミテッド・ライアビリティ・カンパニー Ｐｐａｒモジュレーターとしての化合物および組成物
US7666888B2 (en) 2006-07-20 2010-02-23 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11β-HSD-1

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
A. CORSARO ET AL., JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 26, 1989, PROVO US, pages 1691 - 1699, XP000961272 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080604A1 (fr) * 2002-03-21 2003-10-02 Glaxo Group Limited Composes de tetrahydrofuran de dihydroisoxazolyle substitues utilises en tant qu'intermediaire dans la preparation de derives de 2-(purine-9-yl) - tetrahydrofuran
JP2007537286A (ja) * 2004-05-14 2007-12-20 アイアールエム・リミテッド・ライアビリティ・カンパニー Ｐｐａｒモジュレーターとしての化合物および組成物
EP1745027A4 (fr) * 2004-05-14 2009-06-03 Irm Llc Composes et compositions en tant que modulateurs de ppar
US7820705B2 (en) 2004-05-14 2010-10-26 Irm Llc Compounds and compositions as PPAR modulators
US7666888B2 (en) 2006-07-20 2010-02-23 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11β-HSD-1

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