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WO2006108491A1 - Procede ameliore de preparation de nitriles d'oxazole - Google Patents

Procede ameliore de preparation de nitriles d'oxazole Download PDF

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Publication number
WO2006108491A1
WO2006108491A1 PCT/EP2006/002509 EP2006002509W WO2006108491A1 WO 2006108491 A1 WO2006108491 A1 WO 2006108491A1 EP 2006002509 W EP2006002509 W EP 2006002509W WO 2006108491 A1 WO2006108491 A1 WO 2006108491A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxazole
formula
chloride
phase
nitriles
Prior art date
Application number
PCT/EP2006/002509
Other languages
English (en)
Inventor
Johann Hiebl
Michael Stanek
Jan Hilko Schulte
Original Assignee
Dsm Fine Chemicals Austria Nfg Gmbh & Co Kg
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 Dsm Fine Chemicals Austria Nfg Gmbh & Co Kg filed Critical Dsm Fine Chemicals Austria Nfg Gmbh & Co Kg
Publication of WO2006108491A1 publication Critical patent/WO2006108491A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • Oxazole nitriles such as, for instance, 2- (5-methyl-2- phenyl-1, 3-oxazol-4-yl) acetonitrile, are valuable intermediates in the synthesis of pharmaceuticals which are employed for example for the prophylaxis and/or treatment of diabetes II .
  • the present invention accordingly relates to an improved process for preparing oxazole nitriles of the formula
  • Oxazole nitriles of the formula (I) are prepared by the process of the invention.
  • Ar is aryl or heteroaryl and Rl is H or alkyl .
  • Aryl and heteroaryl mean in this connection aromatic compounds which preferably have 4 to 20 C atoms.
  • the heteroaryl compounds additionally have 1 to 3 heteroatoms from the group of 0, N or S .
  • Possibilities in this connection are monocyclic or polycyclic aromatic groups to which further rings (cycloalkyl, cycloheteroalkyl or heteroaryl) may be fused where appropriate .
  • aromatic compounds examples include phenyl, naphthyl, cyclopentadienyl, indenyl , fluorenyl, indanyl, tetralinyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, indolyl, cumaronyl, quinolinyl, chromenyl , chromanyl, etc.
  • aryl means phenyl or naphthyl and heteroaryl pyridyl .
  • the aryl and heteroaryl radicals may moreover be optionally substituted one or more times.
  • suitable substituents are alkyl, preferably Ci-C 3 -alkyl, alkoxy, preferably Ci-C 6 -alkoxy, halogen such as, for instance, chlorine, bromine or fluorine, mono- or polyhaloalkyl , mono- or polyhaloalkoxy, alkenyl , preferably C 2 -C 8 -alkenyl, optionally substituted phenyl, optionally substituted amine, hydroxy, nitro, carboxyl, carboxylic ester, etc.
  • the aryl or heteroaryl radical is preferably unsubstituted or substituted once or twice by hydroxy, Ci-C 4 -alkyl, C 1 -C 4 -alkoxy, chlorine, trifluoromethyl or phenyl .
  • Rl is H or alkyl, where alkyl means saturated or mono- or polyunsaturated, linear, branched or cyclic hydrocarbon chains having 1 to 20 C atoms, preferably having 1 to 8 C atoms. Examples thereof are methyl, ethyl, i-propyl, tert-butyl, cyclohexyl, propenyl, etc.
  • the inventive preparation of the oxazole nitriles of the formula (I) starts from the corresponding oxazole chloride of the formula (II) .
  • Suitable oxazole chlorides can be prepared as in the prior art as described, for instance, in Chem. Pharm. Bull., 1971, 19, pp. 2050; J. Med. Chem., 1996, 39, pp. 237-245; J. Med. Chem., 2000, 43, p. 995-1010, US 5468760, US 5480896, WO 03/043985, etc.
  • the inventive reaction of the oxazole chlorides of the formula (II) to give the desired oxazole nitriles of the formula (I) takes place in a suitable solvent with an alkali metal cyanide in the presence of a phase- transfer catalyst .
  • Suitable solvents for the inventive process are aromatic hydrocarbons, which may be optionally halogenated, such as, for instance, toluene, xylenes, chlorobenzenes, etc., or mixtures thereof with water.
  • aromatic hydrocarbons which may be optionally halogenated, such as, for instance, toluene, xylenes, chlorobenzenes, etc., or mixtures thereof with water.
  • a mixture of toluene and water is preferably employed as solvent .
  • alkali metal cyanide Suitable examples of alkali metal cyanide are NaCN, LiCN, KCN, etc.
  • the cyanide is in this case employed in at least the equivalent amount or in an excess relative to the oxazole chloride.
  • the cyanide is preferably used in an amount of from 1.0 to 2.5 mol per mol of oxazole chloride and particularly preferably from 1.1 to 1.5 mol per mol of oxazole chloride .
  • Suitable phase-transfer catalysts are quaternary phosphonium salts such as, for instance, (alkyl) 4 P + Hal " , (aryl) 4 P + Hal ⁇ , alkylaryl-P + HaI " , etc. or quaternary ammonium salts such as, for instance, tetraalkylammonium halides, tetraarylammonium halides, alkylarylammonium halides or cyanides, etc., which are described for example in CM. Starks, CL. Liotta, M. C. Halpern, Phase Transfer Catalysis; Chapman & Hall; New York, 1994.
  • Halide means in this case preferably bromide or chloride.
  • the tetraalkyl moiety consists of four alkyl groups, which may be identical or different, and comprise 1 to 16 C atoms.
  • the aryl moiety may be for example phenyl or benzyl .
  • Quaternary ammonium salts are preferably employed.
  • phase-transfer catalysts examples include tetrabutylammonium bromide (TBAB) , tributylmethyl- ammonium chloride (TBMAC) , trimethylbenzylammonium chloride, etc.
  • phase-transfer catalyst is employed in the inventive reaction in an amount of from 0.001 to 0.1 mol per mol of oxazole chloride. An amount of from 0.01 to 0.05 mol per mol of oxazole chloride is preferred.
  • the reaction temperature is 50 to 120 0 C, preferably 75 to 90 0 C.
  • reagents oxazole chloride, solvent, cyanide, phase-transfer catalyst
  • the cyanide can also be added last, at the desired reaction temperature.
  • the reaction mixture is cooled to a temperature of from 5 to 30 0 C, preferably to 15 to 25°C, and an aqueous base such as, for instance, a dilute Na 2 CO 3 or NaHCO 3 solution is added and, after phase separation, the organic phase is, where appropriate after extraction one or more times with the aqueous base, concentrated.
  • suitable solvents for this are diisopropyl ether, tert-butyl methyl ether, methanol, etc.
  • Oxazole nitriles of the formula (I) are prepared in higher yields compared with the prior art, and in high purity, from easily obtainable precursors in a simple manner which is easy to achieve industrially.
  • Ar is aryl or heteroaryl
  • Rl is H or alkyl
  • R2 is alkyl or aryl

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un procédé perfectionné de préparation de nitriles d'oxazole représentés par la formule (I) dans laquelle Ar est aryle ou hétéroaryle et R1 est H ou alkyle, ledit procédé consistant à faire réagir un chlorure d'oxazole représenté par la formule (II) dans laquelle Ar et R1 sont tels que définis ci-dessus, dans un solvant avec un cyanure de métal alcalin, en présence d'un catalyseur à transfert de phase, de manière à produire le nitrile d'oxyzole souhaité de formule (I).
PCT/EP2006/002509 2005-04-11 2006-03-18 Procede ameliore de preparation de nitriles d'oxazole WO2006108491A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT5982005 2005-04-11
ATA598/2005 2005-04-11

Publications (1)

Publication Number Publication Date
WO2006108491A1 true WO2006108491A1 (fr) 2006-10-19

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/002509 WO2006108491A1 (fr) 2005-04-11 2006-03-18 Procede ameliore de preparation de nitriles d'oxazole

Country Status (1)

Country Link
WO (1) WO2006108491A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012153331A2 (fr) 2011-05-09 2012-11-15 Topical Therapeutic Agent (Tta) Ltd. Formulations topiques capturant l'oxyde nitrique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1139940A (en) * 1966-09-30 1969-01-15 Ici Ltd Oxazole derivatives
US4661610A (en) * 1985-07-31 1987-04-28 Basf Aktiengesellschaft Preparation of veratryl cyanide
WO2002018355A1 (fr) * 2000-08-23 2002-03-07 Eli Lilly And Company Dérivés d'acide oxazolyl-aryloxyacétique et leur utilisation comme agonistes des ppar
US20030055265A1 (en) * 2001-05-15 2003-03-20 Alfred Binggeli Oxazole derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1139940A (en) * 1966-09-30 1969-01-15 Ici Ltd Oxazole derivatives
US4661610A (en) * 1985-07-31 1987-04-28 Basf Aktiengesellschaft Preparation of veratryl cyanide
WO2002018355A1 (fr) * 2000-08-23 2002-03-07 Eli Lilly And Company Dérivés d'acide oxazolyl-aryloxyacétique et leur utilisation comme agonistes des ppar
US20030055265A1 (en) * 2001-05-15 2003-03-20 Alfred Binggeli Oxazole derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BROOKS D A ET AL: "Design and synthesis of 2-methyl-2-{4-[2-(5-methyl-2- aryloxazol-4-yl)ethoxy]phenoxy}propionic acids: a new class of dual PPARalpha/gamma agonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, no. 13, 21 June 2001 (2001-06-21), pages 2061 - 2064, XP002184099, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012153331A2 (fr) 2011-05-09 2012-11-15 Topical Therapeutic Agent (Tta) Ltd. Formulations topiques capturant l'oxyde nitrique

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