Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
  • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

• the present invention relates to a process for the preparation of 4-hydroxyquinolines and / or tautomeric forms.
• the invention relates more particularly to 5,7-dichloro-4-hydroxyquinoline and / or its tautomeric forms.
• DCHQ 5,7-dichloro-4-hydroxyquinoline
• the characteristic of the process of the invention is to heat a 4-hydroxyquinoline carboxylic acid, its derivatives or precursors, at a temperature at most equal to 200 ° C. and in the presence of a base.
• a quinoleic compound is used.
• quinoleic compound is meant a heterocyclic compound comprising a quinoline motif. This term is also used for the naphthypyridine type compounds which are also included in the process of the invention.
• the heterocycle of the quinoleic compound carries at least one hydroxyl group in position 4 and a functional group in position ⁇ of the hydroxyl group. Other substituents can also be present in particular in position 5 and / or 7.
• Y As regards the nature of the functional group which is symbolized in the following formula (I) by Y, it is a carboxylic group (COOH), a precursor group (nitrile) or a derivative group ( ester or amide).
• a linear or branched alkenyl group having from 2 to 12 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl, allyl,. a cyclohexyl, phenyl or benzyl group,
• a linear or branched alkoxy or thioether group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy radicals,
• an amino group optionally substituted by alkyl groups having from 1 to 6 carbon atoms,. a halogen atom, preferably a chlorine or bromine atom, . a trifluromethyl group,
• - Y represents one of the following groups:. a CN group, a COOR2- group. a CO NR 3 R 4 group .
• groups, R2, R3 or R4, identical or different represent a hydrogen atom or an alkyl, cyclohexyl, phenyl or benzyl group,
• - n is a number between 1 and 4, preferably equal to 1 or 2.
• substituents in position 5 and / or 7 more particularly suitable are halogen atoms such as fluorine, chlorine, bromine, iodine or a group of type -CFg.
• halogen atoms such as fluorine, chlorine, bromine, iodine or a group of type -CFg.
• the preferred substituents are chlorine atoms, a methyl or methoxy radical.
• R2 As for the nature of R2, R3 or R 4 , it is not critical insofar as the carboxylate group is eliminated. It is for economic reasons, essentially a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, but it is possible to have other groups, for example example cyclohexyl, phenyl or benzyl or other group.
• the starting quinoleic compounds which correspond to formula (I) are known products and which can be obtained in particular by reaction of the substituted anilines on the alkyl aikoxymethylenemalonates (cf. CC Price et al, Organic Synthesis 2, P-272) .
• R ⁇ Y and n have the meanings given above for formula (I).
• the decarboxylation of the quinoleic compound is carried out in the presence of a base.
• a base which can be mineral or organic therefore intervenes in the process of the invention.
• a sufficiently strong base is chosen, that is to say a base whose pKa of the associated acid is greater than or close to 5: the pKa being defined as the cologarithm of the acid dissociation constant measured, in aqueous medium, at 25 ° C.
• alkaline bases derived from alkali metals or alkaline earth metals.
• alkali metals is meant in this text, the elements of column 1A of the periodic table, preferably alkali metals such as lithium, sodium, potassium, rubidium and cesium.
• alkaline earth metals is meant in this text, the elements of column 2A of the periodic table, preferably alkaline earth metals such as beryllium, magnesium, calcium, strontium and barium.
• Use is preferably made, in the process of the invention, of an alkali metal hydroxide, preferably potassium or sodium hydroxide or else a hydrogen carbonate or an alkali metal carbonate, preferably hydrogen carbonate or potassium or sodium.
• an alkali metal hydroxide preferably potassium or sodium hydroxide or else a hydrogen carbonate or an alkali metal carbonate, preferably hydrogen carbonate or potassium or sodium.
• quaternary ammonium hydroxide use is preferably made of tetralkylammonium or trialkylbenzylammonium hydroxides in which the identical or different alkyl radicals represent a linear or branched alkyl chain having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms.
• Tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide is preferably chosen. It is also possible according to the invention to use trialkylbenzylammonium hydroxides and in particular trimethylbenzylammonium hydroxide.
• tri-n-butylamine di-n-butylamine, hexamethylenediamine, cyclohexylamine, N-methylpyrrolidine, 4-dimethylaminopyridine, morpholine, quinoline, pyridine, 3 -picoline, 5-picoline.
• the base is advantageously used in the form of an aqueous solution.
• concentration of the basic solution is preferably between 2 and 45% by weight, and even more preferably between 5 and 30%.
• the amount of base used expressed by the molar ratio between the number of moles of base (or of base equivalents) and the number of moles of quinoleic compound preferably varies between 1 and 6, and more preferably between 1, 5 and 3.5.
• the decarboxylation reaction carried out in the process of the invention is preferably carried out in the presence of water which can be in liquid and / or vapor form.
• the amount of quinoleic compound used preferably represents from 2 to 50%, and even more preferably from 5 to 35% by weight of water.
• the water is provided by the basic solution.
• a first variant consists in carrying out the decarboxylation by heating the reaction mixture comprising the quinoleic compound, the base and the water.
• a third implementation variant of the process of the invention consists in adding to the reaction medium comprising the compound quinoleic, base, water, an organic solvent which can be a water-miscible or immiscible solvent.
• the organic solvent need not dissolve the quinoleic compound.
• an organic solvent, immiscible with water and with a high boiling point, is chosen.
• a preferred solvent for this type of reaction is the eutectic mixture of biphenyl oxide and biphenyl referenced by the trade names of Therminol VP1, Dowtherm or Gilotherm DO.
• the decarboxylation temperature is advantageously chosen in the preferred temperature zone.
• solvents such as, for example, triphenylmethane, sulfolane, benzylbenzene, 1,4-dibenzylbenzene, a silicone oil or petroleum fractions with a high boiling point above the temperature. of reaction chosen.
• Organic solvents such as dimethylformamide or N, N'-diacetamide are also suitable.
• the concentration of the quinoleic compound in the organic solvent is such that the weight ratio between the organic solvent and the quinoleic compound preferably varies between 1 and 30, and even more preferably between 1 and 10.
• the base used is liquid, for example an amine
• another variant which consists in carrying out the decarboxylation by heating the reaction mixture comprising the quinoleic compound and the base, in the absence of water .
• the medium can be liquid, solid or two-phase (liquid / liquid or liquid / solid) or three-phase (liquid / liquid / solid).
• the choice of reactor will be adapted accordingly.
• the reagents are worked under autogenous pressure.
• the decarboxylation operation proper it is carried out by heating the reaction medium.
• the decarboxylation temperature is at most equal to 200 ° C, preferably between 90 ° C and 190 ° C, and even more preferably between 95 ° C and 180 ° C.
• the duration of the heating must be sufficient for the reaction to be sufficiently complete. It should be noted that the process is particularly advantageous in the case of the use of the quinoleic compound in the form of an ester, because due to the presence of the base, the hydrolysis of the ester takes place during of the decarboxylation step, simultaneously and / or successively.
• the product obtained is found in salified form in the aqueous phase which is separated from the organic phase, for example by decantation.
• an acid treatment is carried out in order to recover the desired free product in the form of a precipitate.
• an acid is preferably added, hydrochloric, sulfuric or phosphoric acid, in an amount such that the 4-hydroxyquinoline produced is in free form.
• the concentration of the starting acid is indifferent comprising from 10 to
• an acid solution of dilute concentration preferably from 20 to 50% by weight.
• the precipitate is separated according to conventional solid-liquid separation techniques, preferably by filtration. It may be appropriate to wash the precipitate in order to remove any excess acid used and traces of heavy solvent.
• water and / or a solvent having a low boiling point for example less than 150 ° C and preferably between 60 ° C and 120 ° C, can be used.
• very suitable solvents mention may be made of: o-dichlorobenzene, methylcyclohexane, benzene, toluene, chlorobenzene, methanol or ethanol.
• the decarboxylated product is thus obtained with very good yield.
• the filtrate which contains the base is optionally recyclable in other decarboxylation operations.
• the invention applies very particularly to the preparation of 4-hydroxy-7-halo-quinolines, preferably of 4-hydroxy-7-chloro-quinoline and its isomer, 4-hydroxy-5-halo-quinoline, preferably 4 -hydroxy-5-chloroquinoline. It is quite well suited for the preparation of 5,7-dichloro-4-hydroxyquinoline.
• the transformation rate (TT) corresponds to the ratio between the number of moles of substrate transformed and the number of moles of substrate used.
• the yield (RR) corresponds to the ratio between the number of moles of product formed and the number of moles of substrate used.
• Example 7 Therminol VP1 which is a eutectic mixture of diphenyl and diphenyl oxide.
• the reaction medium is kept under stirring at 70 ° C for 50 min, the precipitate obtained is washed with water and then dried under reduced pressure (10 mm of mercury) at 70 ° C.
• Example 23 a - Preparation of 4-hvdroxv-5.7-dichloro ⁇ uinorial ⁇ ne-3-carboxvlate of ethvle: In a stirred reactor provided with a distillation column, 266 g of
• the temperature of the reaction mixture obtained above is lowered to 95 ° C. and 142.3 g of a 25% aqueous potassium solution (0.638 mol) are added.
• the mixture is heated to 95 ° C-100 ° C for 9 hours and then 28.6 g of the 25% aqueous potassium solution (0.128 mol) are added.
• the mixture is left to settle at 85 ° C. for 2 hours and then the aqueous potassium phase is separated from the Therminol VP1 phase.
• This aqueous phase is acidified with 412 g of a 10.5% aqueous sulfuric acid solution (0.437 mol).
• the precipitate obtained is filtered, washed with water and dried.
• soda is used in place of potash.
• the mixture is stirred at 30 rpm. A suspension is obtained and a gas evolution is observed.
• the autoclave is closed and heated for 45 min to 120 ° C: the pressure is 4.87 Bar.
• the seal is put back on and heated for 2 hours 15 min, up to 150 ° C. by decompressing from time to time (2 times).
• a suspension is obtained which is diluted with 1 liter of water.
• the base introduced at the start is present in the mother liquors which can therefore be recycled in a new decarboxylation step which avoids the rejection of effluents.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Quinoline Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1998
  • 1998-12-01 FR FR9815126A patent/FR2786483B1/fr not_active Expired - Fee Related
• 1999
  • 1999-12-01 CN CN99814001A patent/CN1329598A/zh active Pending
  • 1999-12-01 WO PCT/FR1999/002985 patent/WO2000032576A1/fr not_active Application Discontinuation
  • 1999-12-01 JP JP2000585218A patent/JP2002531440A/ja not_active Withdrawn
  • 1999-12-01 US US09/856,810 patent/US6362340B1/en not_active Expired - Fee Related
  • 1999-12-01 EP EP99973021A patent/EP1135372A1/de not_active Withdrawn
  • 1999-12-01 HU HU0104482A patent/HUP0104482A3/hu unknown
  • 1999-12-01 AU AU13934/00A patent/AU1393400A/en not_active Abandoned

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