EP0182061B1 - Procédé de préparation de l'acide 2-(4-fluorophényl)-alpha-méthyl-5-benzoxazole acétique - Google Patents

Procédé de préparation de l'acide 2-(4-fluorophényl)-alpha-méthyl-5-benzoxazole acétique Download PDF

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Publication number
EP0182061B1
EP0182061B1 EP85112699A EP85112699A EP0182061B1 EP 0182061 B1 EP0182061 B1 EP 0182061B1 EP 85112699 A EP85112699 A EP 85112699A EP 85112699 A EP85112699 A EP 85112699A EP 0182061 B1 EP0182061 B1 EP 0182061B1
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EP
European Patent Office
Prior art keywords
und
von
fluorphenyl
benzoxazol
mit
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Expired - Lifetime
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EP85112699A
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German (de)
English (en)
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EP0182061A1 (fr
Inventor
Roberto Signorini
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Ravizza SpA
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Ravizza SpA
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Priority to AT85112699T priority Critical patent/ATE70832T1/de
Publication of EP0182061A1 publication Critical patent/EP0182061A1/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
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals

Definitions

  • This invention relates to a process for preparing 2(4-fluorophenyl) ⁇ -methyl-5-benzoxazole acetic acid.
  • (+)-2(4-fluorophenyl) ⁇ -methyl-5-benzoxazole acetic acid is known for example from British patent 1,495,488 and Italian patent 22454 A/82.
  • stage A 4-hydroxy-3-aminophenylacetic acid (II) is reacted with 4-fluorobenzoyl chloride (III) to produce 3(4-fluoro)-benzamido-4-hydroxyphenylacetic acid (IV).
  • the reaction is conducted in a reaction medium constituted by a 2%-5% aqueous sodium bicarbonate solution operating at a temperature of between 0° and 30°C, for a time of between 3 and 6 hours.
  • the product (IV) is obtained with a yield of about 95%.
  • stage B in which the heterocyclic ring is formed, the product (IV) is treated with a 70-80 weight % phosphoric acid solution at a temperature of 120°-125°C for a time of between 30 minutes and 1 hour.
  • the product (V) is obtained with a yield of between 90% and 95%.
  • stage C) the product (V) is esterified by treatment with ethyl alcohol in the presence of H2SO4, by heating under reflux for some hours to obtain ethyl (4-fluorophenyl)5-benzoxazole acetate (VI) with a yield of 80%-85%.
  • stage D) the ester (VI) is reacted with diethyloxalate in the presence of sodium methylate in a reaction medium constituted by an ether or an hydrocarbon solvent.
  • a reaction medium constituted by an ether or an hydrocarbon solvent.
  • the mixture is heated to boiling under reflux for 20-30 hours and is then cooled and neutralised with a 5% H2SO4 solution.
  • the organic phase is washed with a saturated NaCl solution and then with H2O and dried by treatment with Na2SO4, after which it is concentrated to a small volume to obtain ethyl 2(4-fluorophenyl)-5-benzoxazole oxalacetate (VII) with a yield of between 90% and 95%.
  • stage E the product (VII) is treated with formaldehyde in an aqueous K2CO3 solution at ambient temperature under agitation, for a time of 4-6 hours.
  • Ethyl 2(4-fluorophenyl)5-benzoxazole acrylate (VIII) is thus obtained, with a yield exceeding 95%.
  • stage F the ester (VIII) is hydrolysed to obtain the corresponding acid by firstly treating it in a tetrahydrofuran solution with a KOH solution at ambient temperature for 20-30 hours and then acidifying with a solution of HCl in t-butylmethylether.
  • stage G the product (IX) is hydrogenated under atmospheric pressure at a temperature of 25°-40°C, using 5% Pd-on-carbon as catalyst in a reaction medium constituted by ethyl alcohol.
  • the catalyst is separated by filtration in a nitrogen environment, and the aqueous solution is used for the reaction with 4-fluorobenzoyl chloride, which is carried out in the following manner: the aqueous solution is cooled to 5°C in a nitrogen environment, 460 ml of t-butylmethylether are added, and then 74 ml of 4-fluorobenzoyl chloride dissolved in 170 ml of t-butylmethylether are fed slowly.
  • the mixture is agitated vigorously for 6 hours at ambient temperature, after which it is filtered to recover the product. A further small quantity of product is recovered from the mother liquors by evaporating the solvent.
  • 127 g of finely ground 3(4-fluoro)benzamido-4-phenylacetic acid are added to 1 litre of a 75 weight % phosphoric acid solution heated to 130°C and under agitation. The heating is continued to 125°C for 30 minutes to obtain complete dissolving, after which the solution is cooled to 50°C and water is slowly added until the product crystallises. Further water is added to form a total quantity of 3 litres, and agitation is continued for 2 hours. The mixture is filtered, the solid is pulped in distilled water, refiltered and dried.
  • the resultant mixture is heated to boiling under reflux for 24 hours, and is then cooled and neutralised with 5% sulphuric acid.
  • the organic phase is washed firstly with a saturated sodium chloride solution and then with water, and is finally dried by treatment with sodium sulphate.
  • the mixture is agitated for 5 hours at ambient temperature and is then extracted with t-butylmethylether.
  • the solution is partly evaporated under vacuum at 40°C, cooled to ambient temperature, 500 ml of t-butylmethylether are added, and the mixture acidified with dilute (1:10) HCl to pH 2.
  • the ether phase is separated, and the aqueous phase is extracted twice with ether.
  • the pooled ether solution is dried and evaporated.
  • the catalyst is separated by filtration, and the solution is concentrated to a small volume.

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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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (6)

  1. Procédé de préparation d'acide 2(4-fluorophényle)α-méthyl-5-benzoxazole acétique, caractérisé en ce qu'on fait d'abord réagir de l'acide 4 -hydroxy-3-amino-phénylacétique avec du chlorure de 4-fluorobenzoyle et on fait réagir le produit obtenu avec de l'acide phosphorique ; on estérifie le 2(4-fluorophényle)5-benzoxazole acétique ainsi obtenu avec de l'alcool éthylique et on traite l'ester avec de l'oxalate de diéthyle ; on fait réagir l'éthyl 2(4-fluorophényle) 5-benzoxazole oxalacetate obtenu avec ou formaldéhyde et du carbonate de potassium pour obtenir de l'éthyl -2(4-fluorophényle)-5-benzoxazole acrylate qu'on hydrolyse pour obtenir l'acide correspondant d'où l'on obtient par hydrogénation l'acide 2(4-fluorophényle) - méthyl-5-benzoxazole acétique.
  2. Procédé selon la revendication 1, caractérisé en ce que ladite réaction entre l'acide 4-hydroxy-3-aminophénylacétique et le chlorure de 4-fluoro-benzoyle est conduite dans un milieu de réaction constitué par une solution aqueuse de bicarbonate de sodium d'une force comprise entre 2 % et 5 %, opérant à une température comprise entre 0 et 30 degrés C pour une durée comprise entre 3 à 6 heures, et le produit ainsi obtenu est traité avec une solution de H₃ PO₄ à 70-80 % en poids, à une température de 120-125 degrés C pour une durée comprise entre 30 minutes et 1 heure.
  3. Procédé selon la revendication 1, caractérisé par le fait que ladite estérification de l'acide 2(4-fluorophényle)5-benzoxazole acétique est conduite en présence de H₂ PO₄ au point d'ébullition sous reflux, pendant quelques heures, et le dit traitement de l'ester avec du diéthyloxalate est conduit en présence de méthylate de sodium dans un milieu de réaction constitué par un éther ou un solvant hydrocarboné au point d'ébullition, sous reflux, pendant 20-30 heures.
  4. Procédé selon la revendication 1, caractérisé par le fait que ladite réaction entre éthyl 2(4-fluorophényle)5-benzoxazole oxalacetéte et formaldéhyde et carbonate de potassium est conduite en solution aqueuse à la température ambiante pendant une durée de 4-6 heures.
  5. Procédé selon la revendication 1, caractérisé par le fait que ladite hydrolyse de l'éthyl-2(4-fluorophényl)5-benzoxazole acrylate est conduite par traitement avec KOH dans un environnement de tétrahydrofuranne à la température ambiante, pendant 20-30 heures, suivi par acidification avec HCl dans du t-butylméthyléther.
  6. Procédé selon la revendication 1, caractérisé par le fait que ladite hydrogénation de l'acide 2(4-fluorophényle)5-benzoxazole acrylique est conduite sous la pression atmosphérique, à une température de 25-40 degrés C, en utilisant un catalyseur sous forme de 5 % Pd sur carbone, dans un milieu de réaction constitué par de l'éther éthylique.
EP85112699A 1984-10-22 1985-10-07 Procédé de préparation de l'acide 2-(4-fluorophényl)-alpha-méthyl-5-benzoxazole acétique Expired - Lifetime EP0182061B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85112699T ATE70832T1 (de) 1984-10-22 1985-10-07 Verfahren zur herstellung von 2-(4-fluorphenyl)alpha-methyl-5-benzoxazolessigs|ure.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2326484 1984-10-22
IT23264/84A IT1177017B (it) 1984-10-22 1984-10-22 Processo per la preparazione dell'acido 2(4-flurofenil)alfa-metil-5-benzox azoloacetico

Publications (2)

Publication Number Publication Date
EP0182061A1 EP0182061A1 (fr) 1986-05-28
EP0182061B1 true EP0182061B1 (fr) 1991-12-27

Family

ID=11205428

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85112699A Expired - Lifetime EP0182061B1 (fr) 1984-10-22 1985-10-07 Procédé de préparation de l'acide 2-(4-fluorophényl)-alpha-méthyl-5-benzoxazole acétique

Country Status (6)

Country Link
US (1) US4652654A (fr)
EP (1) EP0182061B1 (fr)
JP (1) JPS61100574A (fr)
AT (1) ATE70832T1 (fr)
DE (1) DE3585022D1 (fr)
IT (1) IT1177017B (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1233836B (it) * 1988-01-13 1992-04-21 Euroresearch Srl Sali idrosolubili dell'acido (+)2-(4 fluorofenil)-alfa-metil-5 benzoxazolo acetato.
GB9312853D0 (en) * 1993-06-22 1993-08-04 Euro Celtique Sa Chemical compounds
US5591776A (en) * 1994-06-24 1997-01-07 Euro-Celtique, S.A. Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV
US5922751A (en) * 1994-06-24 1999-07-13 Euro-Celtique, S.A. Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same
US5665737B1 (en) * 1994-10-12 1999-02-16 Euro Celtique Sa Substituted benzoxazoles
US6372770B1 (en) 1994-10-12 2002-04-16 Euro-Celtique, S.A. Benzoxazoles
AU699489B2 (en) * 1994-10-12 1998-12-03 Euro-Celtique S.A. Novel benzoxazoles
DE69531506T2 (de) * 1994-12-13 2004-06-24 Euroceltique S.A. Arylthioxanthine
US6025361A (en) * 1994-12-13 2000-02-15 Euro-Celtique, S.A. Trisubstituted thioxanthines
EP0799040B1 (fr) * 1994-12-13 2003-08-20 Euroceltique S.A. Thioxanthines trisubstituees
US6166041A (en) * 1995-10-11 2000-12-26 Euro-Celtique, S.A. 2-heteroaryl and 2-heterocyclic benzoxazoles as PDE IV inhibitors for the treatment of asthma
US6075016A (en) * 1996-04-10 2000-06-13 Euro-Celtique S.A. 6,5-fused aromatic ring systems having enhanced phosphodiesterase IV inhibitory activity
US5864037A (en) 1996-06-06 1999-01-26 Euro-Celtique, S.A. Methods for the synthesis of chemical compounds having PDE-IV inhibitory activity
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
CN1222513C (zh) 1997-02-03 2005-10-12 富士写真菲林株式会社 卤化银彩色照相感光材料和其中所用的菲尼酮化合物以及这类化合物的制备方法
RS52963B (sr) * 2009-05-15 2014-02-28 Sanofi Postupak za dobijanje jedinjenja koje je korisno kao inhibitor tafia

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962452A (en) * 1972-05-18 1976-06-08 Lilly Industries, Ltd. Benzoxazole derivatives as therapeutics
GB1435721A (en) * 1972-05-18 1976-05-12 Lilly Industries Ltd Benzoxazole derivatives
US4025636A (en) * 1973-10-23 1977-05-24 Lilly Industries, Ltd. 2-(Optionally substituted)phenyl-5 or 6-substituted benzoxazoles

Also Published As

Publication number Publication date
US4652654A (en) 1987-03-24
IT1177017B (it) 1987-08-26
JPS61100574A (ja) 1986-05-19
IT8423264A0 (it) 1984-10-22
DE3585022D1 (de) 1992-02-06
EP0182061A1 (fr) 1986-05-28
JPH0368026B2 (fr) 1991-10-25
ATE70832T1 (de) 1992-01-15
IT8423264A1 (it) 1986-04-22

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