WO1995011888A1 - Procede de preparation de derives d'acide 3,4-diaryl-5-isoxazolylacetique - Google Patents

Procede de preparation de derives d'acide 3,4-diaryl-5-isoxazolylacetique Download PDF

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Publication number
WO1995011888A1
WO1995011888A1 PCT/AT1994/000160 AT9400160W WO9511888A1 WO 1995011888 A1 WO1995011888 A1 WO 1995011888A1 AT 9400160 W AT9400160 W AT 9400160W WO 9511888 A1 WO9511888 A1 WO 9511888A1
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WO
WIPO (PCT)
Prior art keywords
general formula
compound
acetic acid
pharmaceutically acceptable
diaryl
Prior art date
Application number
PCT/AT1994/000160
Other languages
German (de)
English (en)
Inventor
Karl Eichinger
Original Assignee
F. Joh. Kwizda Gesellschaft M.B.H.
Taiho Pharmaceutical Co., Ltd.
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 F. Joh. Kwizda Gesellschaft M.B.H., Taiho Pharmaceutical Co., Ltd. filed Critical F. Joh. Kwizda Gesellschaft M.B.H.
Priority to JP7512291A priority Critical patent/JPH09504034A/ja
Priority to KR1019960702091A priority patent/KR960705796A/ko
Priority to AU79333/94A priority patent/AU7933394A/en
Priority to EP94930111A priority patent/EP0725777A1/fr
Publication of WO1995011888A1 publication Critical patent/WO1995011888A1/fr

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Classifications

    • 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
    • C07D261/08—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, 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 present invention relates to a new process for the preparation of 3,4-diaryl-5-isoxazolylacetic acid derivatives.
  • Ar 1 and Ar 2 are the same or different and are selected from phenyl and naphthyl; R 1 , R 2 , R 3 and R 4 are the same or different, represent substituents of Ar 1 and Ar 2 and are selected from hydrogen, halogen, trifluoromethyl, lower alkyl and lower alkoxy, and R 5 are selected is made of hydrogen, lower alkyl and lower alkoxy.
  • the compounds of formula A are prepared by converting a corresponding aryl (aryl-substituted-methyl) ketone, for example deoxybenzoin or deoxyanisoin, into the corresponding oxime, the latter compound being treated with n-butyllithium, the corresponding Dilithium salt is obtained in the reaction mixture. This dilithium salt is then with a low. Alkyl acetate or low.
  • the isoxazole obtained is treated again with nitrogen with n-butyllithium and then with dry ice, so that after working up the desired 3,4-diaryl-5-isoxazole acetic acid or 3,4 -Diaryl-5-isoxazolyl- ⁇ - (lower alkoxy) acetic acid is obtained.
  • a corresponding compound of the formula A can then be obtained by further treatment with n-butyllithium, followed by treatment with a lower alkyl halide, wherein R 5 represents lower alkyl.
  • WO 91/07374 relates to ⁇ , ⁇ -unsaturated ketones and ketoxime derivatives which are useful as intermediates for the preparation of a 3,4-diaryl-5-isoxazolylacetic acid derivative, and to a process for the preparation thereof.
  • WO 91/11443 describes a process for the preparation of isoxazole derivatives, correspondingly substituted ⁇ , ⁇ -unsaturated ketoxime derivatives being oxidized.
  • the isoxazole derivatives obtained are also useful as intermediates for the preparation of 3,4-diaryl-5-isoxazolylacetic acid derivatives.
  • JP-A2-60-075471 describes the preparation of 3,4-diaryl-5-isoxazolylacetic acid derivatives starting from 3,4-diaryl-5-methyl-cyanoisoxazole.
  • JP-A2-03-220180 discloses isoxazoline derivatives as intermediates for the preparation of 3,4-diaryl-5-isoxazolyl-acetic acid derivatives and a process for the preparation of these intermediates, an appropriately substituted ⁇ , ⁇ -unsaturated ketoxime derivative is cyclized.
  • R 1 , R 2 , R 3 and R 4 are the same or different and each represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, Ar 1 and Ar are the same or different and each represents phenyl or naphthyl substituted by R 1 and R 2 or R 3 and R 4 .
  • R 1 , R 2 , R 3 , R 4 , Ar 1 and Ar 2 have the meanings given above, with a 3,3-dialkoxyacrylic acid derivative of the general formula
  • R 5 and R 6 are the same or different and each have a lower.
  • Mean alkyl group and R 7 represents a protective group for the carboxyl group, reacted and the protective group is then removed, a compound of the above general formula (I) is obtained, which is optionally converted into a pharmaceutically acceptable salt thereof.
  • alkyl or lower alkoxy when subsequently lower alkyl or lower alkoxy is mentioned, it means alkyl or alkoxy groups each having 1 to 4 carbon atoms.
  • the protective group used to protect the carboxyl group of dialkoxyacrylic acid can in principle be any protective group for a carboxyl group known in the prior art and stable under the selected reaction conditions or easily removable after reaction, for example the carboxyl group can be esterified, preferably with a low . Alkanol, in particular ethanol.
  • protecting groups would be, for example, the benzyl, nitrobenzyl and tert-butyl ester group.
  • dialkoxyacrylic acids used in each case can easily be prepared from cheap starting materials by processes known per se, for example such a suitable process is described by S. Glickman et al. , J. Amer. Chem. Soc. 1945, 67, page 1019.
  • the various aryl-substituted benzoin oximes are also known from the literature, see for example S. Jankins et al., J. Amer. Chem. Soc. 1933, 55, page 1618 or V. Meyer et al., Ber. German chem. Ges., 1888, 21, page 1295.
  • salt formation processes can be used to prepare the pharmaceutically acceptable salts of the free acids of the compounds of the formula (I), for example the free acids of the formula (I) obtained can be dissolved in methanol and sodium 2-ethylhexanoate can be added, after which, if appropriate after concentrating the solution obtained, the precipitated sodium salt can be filtered off.
  • pharmaceutically acceptable salts include the alkali and alkaline earth salts, for example the sodium, potassium and calcium salts, and the ammonium salts of the compounds of the formula (I).
  • a compound of the formula (II) is preferably used in the process according to the invention, in which R 1 , R 2 , R 3 and R 4 are identical and each represent hydrogen, lower alkoxy or halogen and Ar 1 and Ar 2 are each represented by R and R 2 or R 3 and R 4 represent substituted phenyl.
  • deoxyanisoinoxime is reacted with 3,3-diethoxyacrylic acid ethyl ester and the 3,4-bis (4-methoxyphenyl) -5-isoxazolylacetic acid ethyl ester obtained as an intermediate is immediately converted to 3,4-bis- (4-methoxyphenyl) -5-isoxazolylacetic acid is saponified, and if necessary this is converted into a pharmaceutically acceptable salt thereof.
  • reaction is carried out in the presence of an alkali metal organyl in an anhydrous organic solvent and the subsequent saponification in the presence of an inorganic base in an aqueous organic solvent.
  • Alkali metal organyls suitable in the process according to the invention include lithium organyls, such as lithium alkyls, for example methyl lithium, butyllithium or lithium diisopropylamide, or lithium aryls, for example phenyllithium; Sodium organyls, such as sodium alkyls, for example methyl sodium, or sodium aryls, for example triphenylmethyl sodium, and potassium organyls, such as potassium alkyls or potassium aryls.
  • lithium organyls such as lithium alkyls, for example methyl lithium, butyllithium or lithium diisopropylamide, or lithium aryls, for example phenyllithium
  • Sodium organyls such as sodium alkyls, for example methyl sodium, or sodium aryls, for example triphenylmethyl sodium
  • potassium organyls such as potassium alkyls or potassium aryls.
  • the water-free organic solvent used in the reaction can be, for example, a diethylene glycol monoalkyl ether, such as, for example, diethylene glycol methyl ether or diethylene glycol ethyl ether, or an ethylene glycol dialkyl ether, such as, for example, ethylene glycol dimethyl ether or ethylene glycol diethyl ether, an aliphatic ether, such as, for example, diethyl ether, such as a cyclic ether or tetrahydrofuran, an alkylbenzene such as toluene, or a hydrocarbon such as hexane or cyclohexane.
  • a diethylene glycol monoalkyl ether such as, for example, diethylene glycol methyl ether or diethylene glycol ethyl ether
  • an ethylene glycol dialkyl ether such as, for example, ethylene glycol dimethyl ether or ethylene glycol diethyl ether
  • Alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide or calcium hydroxide, for example, can be used as the inorganic base for the saponification following the reaction, the base preferably being used in the course of the reaction formed alkali metal hydroxide.
  • Aqueous solvents suitable for saponification are known to any person skilled in the art, such as, for example, mixtures of low.
  • the reaction is preferably carried out at a temperature in the range from -70 ° C. to room temperature, more preferably -50 ° C. to 0 ° C., in particular -25 ° C.
  • the ratio of compound (II) to compound (III) is approximately equimolar.
  • the duration of the reaction is between 10 minutes and 5 to 6 hours.
  • the metal organyl is used in about 2 to 3 times the molar amount with respect to the compound of the general formula (II).
  • the process according to the invention is carried out in such a way that the reaction is carried out in the presence of butyllithium in water-free tetrahydrofuran under a nitrogen atmosphere and the saponification in the presence of LiOH in aqueous methanol.

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  • 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

Un nouveau procédé permet de préparer des dérivés d'acide 3,4-diaryl-5-isoxazolylacétique de la formule générale (I) ou un sel pharmaceutiquement acceptable de ceux-ci. Dans la formule (I), R?1, R2, R3 et R4¿ sont identiques ou différents et désignent hydrogène, alkyle inférieur, alcoxy inférieur, halogène ou trifluorométhyle; Ar?1 et Ar2¿ sont identiques ou différents et désignent phényle ou naphthyle substitués par R1 et R2 ou par R3 et R4. Selon ce procédé, on fait réagir des désoxybenzoinoximes substituées de manière appropriée avec un dérivé d'acide 3,3-dialcoxyacrylique à groupe carboxyle protégé, puis on enlève le groupe protégeant le groupe carboxyle. On obtient ainsi un composé correspondant à la formule générale susmentionnée (I) qui peut être converti le cas échéant en un sel pharmaceutiquement acceptable.
PCT/AT1994/000160 1993-10-28 1994-10-28 Procede de preparation de derives d'acide 3,4-diaryl-5-isoxazolylacetique WO1995011888A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP7512291A JPH09504034A (ja) 1993-10-28 1994-10-28 ３，４−ジアリール−５−イソオキサゾリル酢酸誘導体の製造法
KR1019960702091A KR960705796A (ko) 1993-10-28 1994-10-28 3,4-디(di)아릴-5- 이소옥사졸릴 아세트산 유도체의 제조 방법(PROCESS FOR PREPARING 3,4-DIARYL-5-ISOXAZOLYL ACETIC ACID DERIVATIVES)
AU79333/94A AU7933394A (en) 1993-10-28 1994-10-28 Process for preparing 3,4-diaryl-5-isoxazolyl acetic acid derivatives
EP94930111A EP0725777A1 (fr) 1993-10-28 1994-10-28 Procede de preparation de derives d'acide 3,4-diaryl-5-isoxazolylacetique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0217693A AT400032B (de) 1993-10-28 1993-10-28 Verfahren zur herstellung eines 3,4-diaryl-5-isoxazolylessigsäurederivates
ATA2176/93 1993-10-28

Publications (1)

Publication Number Publication Date
WO1995011888A1 true WO1995011888A1 (fr) 1995-05-04

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT1994/000160 WO1995011888A1 (fr) 1993-10-28 1994-10-28 Procede de preparation de derives d'acide 3,4-diaryl-5-isoxazolylacetique

Country Status (9)

Country Link
EP (1) EP0725777A1 (fr)
JP (1) JPH09504034A (fr)
KR (1) KR960705796A (fr)
AT (1) AT400032B (fr)
AU (1) AU7933394A (fr)
CA (1) CA2174506A1 (fr)
HU (1) HU9601100D0 (fr)
PL (1) PL314082A1 (fr)
WO (1) WO1995011888A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0026928A1 (fr) * 1979-10-05 1981-04-15 CDC Life Sciences Inc. Composés d'acide 3,4-diarylisoxazole-5-acétique, procédé de préparation et médicaments les contenant
JPS5657767A (en) * 1979-10-15 1981-05-20 Mitsubishi Chem Ind Ltd Preparation of pyrimidine derivative
JPH03220180A (ja) * 1990-01-24 1991-09-27 Taiho Yakuhin Kogyo Kk イソキサゾリン誘導体
WO1992019604A1 (fr) * 1991-05-01 1992-11-12 Taiho Pharmaceutical Co., Ltd. Nouveau derive d'isoxazole et sel de ce derive

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0026928A1 (fr) * 1979-10-05 1981-04-15 CDC Life Sciences Inc. Composés d'acide 3,4-diarylisoxazole-5-acétique, procédé de préparation et médicaments les contenant
JPS5657767A (en) * 1979-10-15 1981-05-20 Mitsubishi Chem Ind Ltd Preparation of pyrimidine derivative
JPH03220180A (ja) * 1990-01-24 1991-09-27 Taiho Yakuhin Kogyo Kk イソキサゾリン誘導体
WO1992019604A1 (fr) * 1991-05-01 1992-11-12 Taiho Pharmaceutical Co., Ltd. Nouveau derive d'isoxazole et sel de ce derive
EP0633254A1 (fr) * 1991-05-01 1995-01-11 Taiho Pharmaceutical Co., Ltd. Nouveau derive d'isoxazole et sel de ce derive

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 116, no. 12, 30 March 1992, Columbus, Ohio, US; abstract no. 128944s, HAGIWARA Y. ET AL.: "Preparation of isoxazoline derivatives as intermediates for antiinflammatory agents, analgesics, and antipyretics." page 894; column 1; *
PATENT ABSTRACTS OF JAPAN vol. 5, no. 120 (C - 065) 4 August 1981 (1981-08-04) *

Also Published As

Publication number Publication date
AT400032B (de) 1995-09-25
CA2174506A1 (en) 1995-05-04
HU9601100D0 (en) 1996-06-28
PL314082A1 (en) 1996-08-19
JPH09504034A (ja) 1997-04-22
ATA217693A (de) 1995-01-15
AU7933394A (en) 1995-05-22
KR960705796A (ko) 1996-11-08
EP0725777A1 (fr) 1996-08-14

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