The present invention relates to a process for preparing 4-hydroxyquinolines and/or their tautomeric forms. More particularly, the invention relates to 5,7-dichloro-4-hydroxyquinoline and/or its tautomeric forms.
5,7-dichloro-4-hydroxyquinoline (DCHQ) is an intermediate used in the plant protection field.
The industrial scale preparation of such a product is a problem, and existing processes are in need of refining.
C. C. Price et al. (Organic Synthesis 3, p. 272) disclose the preparation of 4-hydroxyquinolines using a process consisting of decarboxylation of 4-hydroxy-3-quinolinecarboxylic acids that have been obtained by alkaline or acid hydrolysis of the corresponding esters. However, decarboxylation is carried out at a high temperature of more than 230xc2x0 C.
U.S. Pat. No. 5,731,440 proposes improving that process by carrying out the decarboxylation step at a lower temperature in the range 120xc2x0 C. to 165xc2x0 C., but uses a strong acid medium such as sulphuric acid, phosphoric acid or hydrochloric acid. The disadvantage of that process is that the medium is highly corrosive because of the presence of a strong acid.
The Applicant has discovered an improved hydroxyquinoline preparation process.
The process of the invention is characterized in that a 4-hydroxyquinolinecarboxylic acid, a derivative or precursor thereof, is heated to a temperature of at most 200xc2x0 C. in the presence of a base.
It has unexpectedly been discovered that it is possible to carry out decarboxylation of 4-hydroxyquinolinecarboxylic acids and esters thereof at a low temperature, advantageously in the range 90xc2x0 C. to 160xc2x0 C., in good reaction yields. This is of enormous advantage from an industrial viewpoint.
The process of the invention uses a quinolinic compound.
The term xe2x80x9cquinolinic compoundxe2x80x9d means a heterocyclic compound comprising a quinoline moiety. This term is also used for naphthpyridine type compounds that are also included in the scope of the process of the invention.
The heterocycle of the quinolinic compound carries at least one hydroxyl group in the 4-position and a functional group in the position xcex1 to the hydroxyl group. Other substituents can also be present in particular in the 5- and/or 7-position.
Regarding the nature of the functional group that is shown in formula (I) below by the symbol Y, this is a carboxylic group (COOH), a precursor group (nitrile) or a derivative group (ester or amide).
The starting quinolinic compound of the invention can be represented by the following general formula: 
in which formula (I):
R1, which may be identical or different, represents:
a linear or branched alkyl group containing 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl;
a linear or branched alkyl group carrying one or more halogen atoms, containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl;
a linear or branched alkenyl group containing 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, such as vinyl or allyl,
a cyclohexyl, phenyl or benzyl group;
a linear or branched alkoxy or thioether group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy, ethoxy, propoxy, isopropoxy or butoxy radical;
an acyl group containing 2 to 6 carbon atoms;
a nitro group;
an amino group, optionally substituted by alkyl groups containing 1 to 6 carbon atoms;
a halogen atom, preferably a chlorine or bromine atom;
a trifluoromethyl group;
an alkenylene group containing 3 or 4 carbon atoms that can form a ring with the carbon atoms adjacent to the phenyl ring;
Y represents one of the following groups:
a CN group;
a COOR2 group;
a CONR3R4 group;
in which groups R2, R3 or R4, which may be identical or different, represent a hydrogen atom or an alkyl, cyclohexyl, phenyl or benzyl group;
n is a number in the range 1 to 4, preferably 1 or 2.
Particularly suitable substituents in the 5- and/or 7-position are halogen atoms such as fluorine, chlorine, bromine, iodine or a xe2x80x94CF3 type group.
Preferred non-limiting illustrative examples from the list of substituents are the chlorine atom, methyl radical and methoxy radical.
The nature of R2, R3 and R4 is not critical provided that the carboxylate group is eliminated. For reasons of economy, it is usually a linear or branched alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, but it is possible to use other groups, for example cyclohexyl, phenyl or benzyl groups, or any other group.
More particular compounds with formula (I) for use in the process of the invention that can be cited are 4-hydroxy-5,7-dichloroquinoline-3-carboxylic acid, and methyl or ethyl 4-hydroxy-5,7-dichloroquinoline-3-carboxylate.
The starting quinolinic compounds with formula (I) are known products that can in particular be obtained by reacting substituted anilines with alkyl alkoxymethylenemalonates (cf. C. C. Price et al., Organic Synthesis 3, p. 272).
It should be noted that the invention is applicable to quinolinic compounds with formula (I) and also to tautomeric forms that can be represented by formula (II): 
in which formula (II), R1, Y and n have the meanings given above for formula (I).
In accordance with the process of the invention, the quinolinic compound is decarboxylated in the presence of a base.
A mineral or organic base can be used in the process of the invention.
Preferably, a sufficiently strong base is selected, i.e., a base with an associated acid the pKa of which is more than 5 or close to 5: the pKa is defined as the cologarithm of the dissociation constant of the acid, in an aqueous medium, at 25xc2x0 C.
Particularly suitable bases for carrying out the process of the invention that can be cited are alkaline bases derived from alkali metals or alkaline-earth metals.
The term xe2x80x9calkali metalsxe2x80x9d as used in the present text means elements from column 1A of the periodic table, preferably alkali metals such as lithium, sodium, potassium, rubidium and caesium.
The term xe2x80x9calkaline-earth metalxe2x80x9d as used in the present text means elements from column 2A of the periodic table, preferably alkaline-earth metals such as beryllium, magnesium, calcium, strontium and barium.
For a definition of the elements, reference should be made to the periodic table published in the xe2x80x9cBulletin de la Socixc3xa9txc3xa9 Chimique de Francexe2x80x9d, No 1, (1966).
The process of the invention preferably employs an alkali metal hydroxide, preferably potassium hydroxide or sodium hydroxide, or an alkali metal bicarbonate or carbonate, preferably potassium or sodium bicarbonate or carbonate.
It is also possible to use a quaternary ammonium hydroxide.
Examples of quaternary ammonium hydroxides that are preferably used are tetraalkylammonium or trialkylbenzylammonium hydroxides wherein the alkyl radicals, which may be identical or different, represent a linear or branched alkyl chain containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms.
Preferably, tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide are used.
It is also possible to use trialkylbenzylammonium hydroxides, in particular trimethylbenzylammonium hydroxide.
The process of the invention can also employ monofunctional or bifunctional primary, secondary or tertiary aliphatic, carbocyclic or heterocyclic, aromatic or non aromatic amines.
More specific examples that can be mentioned are tri-n-butylamine, di-n-butylamine, hexamethylenediamine, cyclohexylamine, N-methylpyrrolidine, 4-dimethylaminopyridine, morpholine, quinoline, pyridine, 3-picoline and 5-picoline.
From an economic and practical viewpoint, the base that is selected is preferably potassium or sodium hydroxide.
The base is advantageously used in the form of an aqueous solution.
The concentration of the basic solution is preferably in the range 2% to 45% by weight, more preferably in the range 5% to 30%.
The quantity of based used, expressed as the mole ratio between the number of moles of base (or equivalents of base) and the number of moles of quinolinic compound, is preferably in the range 1 to 6, more preferably in the range 1.5 to 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 the liquid and/or vapour form.
The quantity of quinolinic compound used preferably represents 2% to 50%, more preferably 5% to 35% by weight of the weight of the water.
Preferably, the water is supplied by the basic solution.
The process of the invention can be implemented in a number of ways.
In a first variation, decarboxylation is carried out by heating the reaction mixture including the quinolinic compound, the base and water.
In a second variation, the quinolinic compound and the base are mixed in aqueous solution, the water is evaporated off then the decarboxylation reaction is effected by heating in a completely solid medium.
Finally, in a third variation of the process of the invention, an organic solvent that may or may not be miscible with water is added to a reaction medium including the quinolinic compound, base, and water.
The organic solvent does not have to dissolve the quinolinic compound.
Preferably, an organic solvent is selected that is not miscible with water and has a high boiling point.
A preferred solvent for this type of reaction is a eutectic mixture of biphenyl oxide and biphenyl sold under the trade names of THERMINOL VP1, DOWTHERM or GILOTHERM DO. When used, the decarboxylation temperature is advantageously selected so as to be in the preferred temperature zone.
It is also possible to use other solvents such as triphenylmethane, sulpholane, benzylbenzene, 1,4-dibenzylbenzene, a silicone oil or petroleum cuts with a high boiling point of more than the selected reaction temperature.
Organic solvents such as dimethylformamide or N,Nxe2x80x2-diacetamide are also suitable.
An alcohol type solvent is also suitable, more particularly propanol, isopropanol or n-butanol.
The concentration of quinolinic compound in the organic solvent is such that the weight ratio between the organic solvent and the quinolinic compound is preferably in the range 1 to 30, more preferably in the range 1 to 10.
If the base used is liquid, for example an amine, it is also possible to implement a further variation which consists of carrying out decarboxylation by heating the reaction mixture comprising the quinolinic compound and a base, in the absence of water.
Thus, depending on the implementations of the invention, the medium can be liquid, solid or two-phase (liquid/liquid or liquid/solid) or even three-phase (liquid/liquid/solid). Thus the choice of reactor will be adapted as a consequence.
The reaction is carried out under autogenous pressure.
Regarding the decarboxylation operation proper, it is carried out by heating the reaction medium. The decarboxylation temperature is at most 200xc2x0 C., preferably in the range 90xc2x0 C. to 190xc2x0 C., and more preferably in the range 95xc2x0 C. to 180xc2x0 C.
The heating period must be sufficient for the reaction to be completed to a sufficient degree.
It should be noted that the process is of particular importance when using a quinolinic compound in the form of an ester, as because of the presence of the base, ester hydrolysis occurs during the decarboxylation step, simultaneously and/or successively.
At the end of the operation, depending on the quantity of base used, a product is obtained in the free (acid) form or salt form that essentially comprises the desired quinolinic compound (B) in equilibrium with its tautomeric form (A), with the following formulae: 
where R1 and n have the meanings given above and M represents a hydrogen atom or the cation of the base introduced initially. This cation is preferably an alkali metal if the base used initially is an alkali metal hydroxide, as indicated above.
At the end of the reaction, the reaction medium is treated conventionally.
Thus, when the organic phase is present and when the base is used in excess, the product obtained is in the form of the salt in the aqueous phase which is separated from the organic phase, for example by decanting.
When the base is in excess, acid treatment is carried out to recover the desired free product in the form of a precipitate.
To this end, an acid is added, preferably hydrochloric acid, sulphuric acid or phosphoric acid, in a quantity such that the 4-hydroxyquinoline produced is in the free form.
The concentration of the starting acid is anywhere in the range 10% to 90% by weight of acid, but preferably, a dilute acid solution is used, preferably 20% to 50% by weight.
The precipitate is separated using conventional solid-liquid separation techniques, preferably by filtering.
Washing the precipitate to eliminate traces of organic liquid may be desirable. To this end, water or a solvent with a low boiling point can be used, for example less than 150xc2x0 C., preferably in the range 60xc2x0 C. to 120xc2x0 C. Particular examples of eminently suitable solvents are: o-dichlorobenzene, methylcyclohexane, benzene, toluene, chlorobenzene, methanol and ethanol.
The decarboxylated product is obtained in a very high yield.
When the base is not used in excess, acid does not need to be added. The free quinolinic compound is obtained directly in the form of a precipitate which only needs separation, for example by filtering.
The filtrate which contains the base is optionally recycled to other decarboxylation operations.
The invention is particularly suitable for the preparation of a 4-hydroxy-7-halogenoquinolines, preferably 4-hydroxy-7-chloroquinoline and its isomer, or a 4-hydroxy-5-halogenoquinoline, preferably 4-hydroxy-5-chloroquinoline. It is eminently suitable for preparing 5,7-dichloro-4-hydroxyquinoline.
USPTO Backgrounds
USPTO Backgrounds