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 new process for preparing 2(4-fluorophenyl) ⁇ -methyl-5-benzoxazole acetic acid.
• (+)-2(4-fluorophenyl)d-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 95X.
• stage B in which the heterocyclic ring is formed, the product (IV) is treated with a 70-80 weight 2 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 H 2 S0 4 , 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% H 2 SO 4 solution.
• the organic phase is washed with a saturated NaCl solution and then with H 2 0 and dried by treatment with Na 2 SO 4' 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 K 2 CO 3 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.
• the resultant mixture is heated to boiling under reflux for 24 hours, and is then cooled and neutralised with 5X 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) HC1 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 residue is taken up in diisopropylether.
• the catalyst is separated by filtration, and the solution is concentrated to a small volume.

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

Priority Applications (1)

Applications Claiming Priority (2)

Publications (2)

Family

ID=11205428

Family Applications (1)

Country Status (6)

Families Citing this family (16)

Family Cites Families (3)

• 1984
  • 1984-10-22 IT IT23264/84A patent/IT1177017B/it active
• 1985
  • 1985-10-07 US US06/784,892 patent/US4652654A/en not_active Expired - Lifetime
  • 1985-10-07 EP EP85112699A patent/EP0182061B1/de not_active Expired - Lifetime
  • 1985-10-07 DE DE8585112699T patent/DE3585022D1/de not_active Expired - Fee Related
  • 1985-10-07 AT AT85112699T patent/ATE70832T1/de not_active IP Right Cessation
  • 1985-10-18 JP JP60231423A patent/JPS61100574A/ja active Granted

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events