ITTO980522A1 - PREPARATION PROCEDURE FOR TYPE 4- (ALCHIL) -3-ALCOS- SI-ANILINE COMPOUNDS. - Google Patents

Description

DESCRIPTION of the industrial invention entitled: "Process for the preparation of 4- (alkyl) -3-alkoxy-aniline compounds",

DESCRIPTION

The present invention relates to a process for preparing compounds of the 4- (alkyl) -3-alkoxy-aniline type starting from metaaminophenol.

More precisely, the invention refers to the synthesis of disubstituted anilines corresponding to the general formula (I):

m which:

- R1 represents a linear or branched C1-10 alkyl group; an aryl group in which the alkyl part is linear and comprises from 1 to 3 carbon atoms and the aryl part is selected from phenyl groups, substituted or not, especially by one or more C1-3 alkyl groups, by one or more atoms halogen or one or more nitro radicals.

- R2 represents a linear or branched C1-16 alkyl group.

The compounds of formula (I) are known and constitute very interesting synthesis intermediates which can especially be condensed with compounds of the alkoxyalkylidenemalonate type, then cyclized to obtain derivatives of quinolein or quinolone, widely used in the field of human health and in that of animal health.

Among these derivatives, the esters of 4-hydroxyquinolein-3-carboxylic acids, such as methylbenzoquate (methyl ester of 7-benzyloxy-6-butyl-1,4-dihydro-4-oxo-3-quinolein carboxylic acid ) which serve, in the field of animal health, especially as anticoccidiosis, used in the feeding of battery pack birds.

The French patent n. 1487 336 (ICI Ltd) which describes the preparation of quinolein derivatives of the 7-alkoxy-4-hydroxy-3-quinolein carboxylic acid ester type, starting from 3-acetylaminophenol.

This synthesis comprises the reaction of a suitably substituted aniline in position 3 and possibly in position 4 with respect to the aramine function found on the ring, with an alkoxymethylenmalonate derivative, then the hot cyclization of the product obtained.

According to this document, the desired substituted aniline is obtained by O-alkylation of the hydroxyl function of 3-acetylaminophenol by means of an allyl halide, transposition to obtain the corresponding 4-substituted 3-hydroxyacetanilide, then new O-substitution of the hydroxyl function for by means of a suitable halide and finally the liberation of the amine function by hydrolysis.

This synthesis requires an important number of phases, some of which are not selective and lead to obtaining isomers or by-products that must be separated.

The object of the present invention is to provide a process for the synthesis of substituted anilines which is simple and relatively inexpensive, and which especially requires a limited number of operations.

Another object of the invention is to provide a process which allows to obtain the desired products with higher yields and which is easy to carry out from the industrial point of view.

For this purpose, the invention intends to provide a process for the preparation of compounds of formula (I) such as the one defined above, characterized in that it comprises the following steps:

1) to acylate the amino function and the hydroxyl function of the following metaminophenol of formula (II):

with the same acylation reagent derived from the R2C = 0 group, in a single step to obtain a compound of formula (III):

2) carry out a Fries transposition reaction by heating the resulting compound (III) in the presence of a Friedel and Crafts type catalyst to form the following compound (IV):

3) selectively reduce the carbonyl function in position 4 of the obtained compound (IV), to form the following compound (V):

4) alkylate the hydroxyl function at 0 and deprotect the amino function of compound (V) by hydrolysis in an alkaline medium to obtain the desired compound (I).

The inventors have now found that it is possible to improve this synthesis route by increasing the general efficiency thanks to the previous process.

The invention is described in more detail below.

It provides a process for the preparation of compounds of formula (I) starting from metaaminophenol (II).

According to the invention, the R1 group is preferably selected from the linear or branched alkyl or aralkyl groups, such as methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene, 3-phenylpropyl, p-methylbenzyl, p-chlorobenzyl, or chlorobenzyl, or, p-dichlorobenzyl, p-nitrobenzyl, decyl, and more preferably still represents the benzyl group.

The R2 group preferably represents a linear or branched C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertzbutyl, pentyl, 1-ethylpropyl, hexyl, and more preferably still represents the n-propyl group.

The process according to the invention is schematized as follows:

Phase 1

In this phase, the amino function is protected and the hydroxyl function of metaminophenol is acylated with the same acylation reagent.

whose acyl group (R2C = 0) has the same number of carbon atoms as that of the alkyl group to be introduced in position 4.

The acylation reagent is advantageously an anhydride of formula (R2C = 0) 20. In this case, R2 advantageously represents a linear or branched C1-6 alkyl group.

It is used in at least stoichiometric quantities and preferably in quantities of at least 2 equivalents, often around 2.2 equivalents.

A carboxylic acid chloride (R2C0C1) can also be used.

In general it is convenient to make the metaamyrophenol react with the acylation reagent with reaction times ranging from 1 to 2 hours and with very high temperatures, generally comprising between 100 ° C and 200 ° C, preferably at the boiling temperature of the reaction solvent. .

According to an advantageous embodiment of the invention, the reaction solvent consists of the same acylation reagent associated with the corresponding carboxylic acid.

Phase 2

A rearrangement of the phenolic ester (III) formed during the first phase is caused by heating it in the presence of a Friedel and Crafts type catalyst. In this way a Fries transposition reaction is carried out.

This reaction normally leads to obtaining ortho- and para- acylphenols, but in the case of a doubly acylated aminophenol, it is observed that the ortho position of the oxygen atom (in para of the nitrogen atom) is favored thanks to the effect steric of the acyl group fixed on nitrogen.

This regioselectivity in favor of position 4 is all the greater the more voluminous the -C (= 0) R2 group fixed to nitrogen is.

The catalyst is preferably aluminum chloride A1C13. Two equivalents of catalyst with respect to metaaminophenol are advantageously used.

For this reaction it is possible to use a solvent usually used for the Fries reactions and the Friedel and Crafts acylations, such as nitrobenzene, dichloromethane, 1,2-dichloroethane, chlorobenzene and dichlorobenzene, preferably dichlorobenzene.

The reaction mixture is then hydrolyzed to obtain compound (IV).

Phase 3

This step consists in carrying out a reduction of the acyl group in the 4 position of the compound (IV).

The reduction reaction is advantageously carried out by hydrogenation in the presence of an industrial catalyst, especially of the palladium coal type.

To carry out this reaction, a hydrogen pressure of between 4 and 20 bars is used, preferably of the order of 12 bars.

Palladium carbon with titers corresponding to those usually used in industrial processes, namely 5 and 10%, with 50% humidity, is preferably used as catalyst. The catalyst is used in a proportion of 1 to 2% (w / w) of metal with respect to the product to be hydrogenated and preferably in a proportion of between 1.4 and 1.6%.

The reaction is carried out in the presence of an acid, selected for example from sulfuric, phosphoric or acetic acid, and preferably in the presence of phosphoric or acetic acid. The acid is advantageously introduced in proportions ranging from 0.5 to 2.5% by mol with respect to the product to be hydrogenated, and preferably in a proportion of about 1.5%.

The reaction is carried out in a protic solvent among which the lower alcohols can be mentioned, especially methanol and ethanol, monoglyme (methyl ether of ethylene glycol), monoisopropylglycol and 1-methoxy-2-propanol, with preference for methanol or ethanol.

The reaction temperature can be between 50 and 100 ° C, and is preferably around 85 ° C.

It is possible to recover the hydrogenated compound (V) in solid form by simple precipitation in water.

Phase 4

This last phase consists in the substitution in 0 of the free hydroxyl function of the compound (V) previously obtained in phase 3, and in the deprotection of the amino function.

To do this, a chloride-type compound of formula R1C1 is advantageously used, suitable according to the final desired compound (I), which is reacted with compound (V) in the presence of a base such as NaOH, KOH, Na2CO3 or K2CO3, in particular K2CO3.

This reaction is carried out in an aprotic solvent such as acetone, acetonitrile or dimethylformamide (DMF), advantageously in dimethylformamide at a temperature between 50 and 100 ° C, preferably of the order of 60 ° C.

The reaction time is generally between 4 and 8 hours, on average between 5 and 6 hours.

An excess of chloride (R1Cl), between 1.4 and 1.9 equivalents, preferably 1.5 equivalents, is advantageously used.

The base is used in an excess of 1 to 2 equivalents, preferably 1.7 equivalents.

The O-substituted product in position 3 may not be isolated, in which case it is reacted directly with a base for deprotection of the amino function.

It is then made to react advantageously with 5 base equivalents, for example NaOH or KOH, in a hydroxyl solvent preferably selected from water, ethanol, 2-methoxyethanol (methylcellosolve) and 1-methoxy-2-propanol.

The reaction lasts from 8 to 12 hours between 85 and 115 ° C. Compound (I) is thus obtained.

According to the invention, a purification of this intermediate (I) is advantageously provided, for example by precipitation with formation of the corresponding hydrochloride:

The compounds of formula (I) constitute synthesis intermediates particularly useful in the preparation of esters of 4-hydroxyquinolein-3-carboxylic acids or analogues.

These esters are generally obtained by reaction of a compound of the dialkylalkoxyalkylidene malonate type with a compound of the substituted aniline type of formula (I) with subsequent cyclization such as that described especially in the previously mentioned document FR-A-1487 336.

The invention also has as its object the use of a compound of formula (I) to obtain derivatives of this type.

The invention also has as its object a process for preparing derivatives of this type of quinolein, especially esters of 4-hydroxyquinolein-3-carboxylic acids, carrying out the steps of the process described above.

The process according to the invention is applied more particularly to the synthesis of 3- (benzyloxy) -4- (n-butyl) aniline of formula (I '), which constitutes a fundamental intermediate in the synthesis of methylbenzoquate.

The invention is illustrated by means of examples, given hereinafter by way of non-limiting purposes.

EXAMPLES

Example 1: Preparation of 3- (benzyloxy) -4- (nbutyl) aniline (I ')

The phenolic ester obtained from phase 1 is subjected to a rearrangement of Fries, using two equivalents of A1C13 at 99% with respect to the starting metaaminophenol.

During the addition of the aluminum chloride, the temperature is maintained at 65 ° C ± 5 ° C, then it is raised up to 130 ° C.

Then 0.15 equivalents of butyryl chloride are added and the reaction mixture is kept at 125-130 ° C for 45 minutes.

The reaction mixture is then hydrolyzed into a water-propanol-mono or dichlorobenzene mixture.

The rearranged product (IV ') crystallizes and can be isolated by ...

In a 100 cc Sotelem stainless steel reactor, 4.5 g of the product (IV ') obtained from phase 2, 1.1 g of 10% palladium carbon with 50% humidity, 40 ml of absolute ethanol and 1.77 g of an ethanolic solution of phosphoric acid (1.47% w / w in absolute ethanol). After closing the reactor, the system is washed with nitrogen and three times with hydrogen before setting the pressure at 12 bar. The heating and stirring are started (1500 rpm). From 50 ° C the decrease is noted

of hydrogen pressure. The reactor pressure is brought back to 12 bar when the pressure has dropped to 7.5 bar. The temperature continues to rise up to 85 ° C and, when there is no longer any decrease in pressure, the heating is interrupted, the temperature is allowed to drop to 20 ° C, the hydrogen is carefully vented and washed with nitrogen. The reaction mass is filtered on sintered glass to recover the catalyst. The filtrate is neutralized with N / 2 soda. This filtrate is then brought to the reflux of the ethanol for 15 minutes and poured into 200 ml of cold water. The product precipitates and is left under stirring for half a day before filtering it through a buchner funnel. 3.54 g of hydrogenated product are collected. The purity, according to HPLC, is 90%, with a corresponding yield of the pure product of 75%.

In a 100 ml reactor equipped with stirrer and coolant, 3 g (12.7 mmoles) of the compound (V ') obtained in step 3, 15 ml, of DMF are introduced

3.6 g of K2CO3 (26 mmol) and 3 g of bendyl chloride (24 mmol). The mixture is stirred at 60 ° C for 6 hours. The K2CO3 is separated by filtration, concentrated under vacuum and the temperature is brought up to 125 ° C. 15 ml of ethanol are added which are then eliminated by distillation under vacuum.

Another 15 ml of ethanol are added and the mixture is heated at 80-85 ° C for 30 minutes under nitrogen. It is cooled to 30 ° C and 3 g of KOH (53 mmoles) in 3 ml of water are added. It is left under stirring under nitrogen at 85 ° C for one night.

It is distilled up to an internal temperature of 115 ° C. It is allowed to cool and water and toluene are added. The two phases are separated, the aqueous phase is extracted, the organic phases are gathered and concentrated to dryness.

Another 15 ml of toluene, 2 ml of isopropanol and 5 ml of 33% hydrochloric acid are added. It is heated under stirring at 70 ° C for a time between 30 minutes and 1 hour, then it is left to cool overnight. The obtained crystals are filtered, washed with 10 ml of toluene and 15 ml of water. It is dried at 60 ° C collecting 2.75 g of product (I ') in the form of crystalline hydrochloride, with purity, evaluated by HPLC, higher than 97%. Yield: 74%.

Examples 2 to 5 illustrate implementation variations of step 3 of the process according to the invention. The other steps can be carried out as in Example 1.

Example 2:

In a 100 cc Sotelem stainless steel reactor, 4.5 g of BuHBP, 1.35 g of 10% palladium carbon with 50% moisture, 20 ml of MeOH spectrosol and 1.25 g of a methanolic solution of phosphoric acid (1.47% w / w in the spectrosol methanol). One proceeds as in Example 1. 3.71 g of hydrogenated product are collected. The purity according to HPLC is 92%, from which a yield in pure product of 80% derives. Example 3:

In a 100 cc Sotelem stainless steel reactor, 4.5 g of BuHBP, 1.49 g of 10% palladium carbon with 50% moisture, 20 ml of MeOH spectrosol and 0.63 g of a methanolic solution of phosphoric acid (1.47% w / w in the spectrosol methanol). One proceeds as in Example 1. 3.77 g of hydrogenated product are collected. The purity according to HPLC is 93%, hence a yield in pure product of 83%.

Example 4:

In a 300 cc Sotelera stainless steel reactor, 13.5 g of BuHBP, 4.47 g of 10% palladium carbon with 50% humidity, .60 ml of MeOH spectrosol and 5.64 g are loaded in succession. of a methanolic solution of phosphoric acid (1.47% w / w in the spectrosol methanol). One proceeds as in Example 1. It is precipitated in 600 ml of cold water. 12 g of hydrogenated product are collected. The purity, according to HPLC is 96%, from which a yield in pure product of 90% is calculated.

Example 5:

In a 100 cc Sotelem stainless steel reactor, 4.5 g of BuHBP, 1.49 g of 10% palladium carbon with 50% moisture, 20 ml of methoxypropan-2-ol and 1 88 g of a phosphoric acid solution (1.47% w / w in methoxypropan-2-ol). One proceeds as in Example 1. 3.93 g of hydrogenated product are collected. The purity, according to HPLC, is 70%, from which a yield in pure product of 65% is calculated.

Examples 6 and 7 illustrate implementation variations of step 4 of the process according to the invention. The other steps can be carried out as in Example 1.

Example 6:

3 g (12.7 mmoles) of the compound (Vf) obtained from phase 3, 15 ml of DMF, 3 g of K2C03 (21.6 mmoles) and 2.4 are charged into a 100 ml reactor equipped with stirring and refrigerant. g of benzyl chloride (19.2 mmoles). The mixture is stirred at 60 ° C for 6 hours. The potassium carbonate is separated by filtration, concentrated under vacuum, the temperature is increased up to 125 ° C. 15 ml of ethanol are added which are then removed by distillation under vacuum.

25 ml of 2-methoxyethanol and 3.6 g of KOH (63.6 mmoles) are added. It is left under stirring under nitrogen at 120 ° C one night. It is concentrated, left to cool and water and toluene are added. The aqueous phase is separated, extracted and the organic phases are gathered and concentrated to dryness.

15 ml of toluene, 2 ml of isopropanol and 5 ml of 33% hydrochloric acid are added. It is heated under stirring to 70 ° C for 30 minutes, then it is left to cool overnight. The obtained crystals are filtered, washed with 10 ml of toluene and 15 ml of water. It is dried at 60 ° C and 3 g of 3- (benzyloxy) -4- (n-butyl) aniline hydrochloride are collected.

Yield: 75%.

Example 7:

One proceeds as in Example 6, but using 1-methoxy-2-propanol (MPG) instead of 2-methoxyethanol.

Yield: 81%.

Claims (18)

CLAIMS 1. Preparation process of a compound having the following formula (I): in which: - R1 represents a linear or branched alkyl group having from 1 to 10 carbon atoms; an aralkyl group in which the alkyl part is linear and comprises from 1 to 3 carbon atoms and the aryl part is selected from the phenyl groups, substituted or not, especially by one or more C1-3 alkyl groups, by one or more atoms halogen or one or more nitro radicals. - R2 represents an alkyl group, linear or branched, having from 1 to 16 carbon atoms, characterized in that it comprises the phases consisting of: 1) to acylate the aramine function and the hydroxyl function of the metaaminophenol having the following formula (II): by means of the same acylation reagent derived from the RzC = 0 group, in a single phase, to form a compound of formula (III): 2) carry out a Fries transposition reaction by heating the compound (III) obtained in the presence of a Friedel and Crafts type catalyst to form the following compound (IV): 3) selectively reduce the carbonyl function in position 4 of the obtained compound (IV), to form the following compound (V): 4) alkylate the hydroxyl function in 0 and deprotect the amino function of compound (V) by hydrolysis in basic medium to obtain the desired compound (I). 2. Process according to claim 1, characterized in that the acylation reagent in phase 1 is an anhydride of formula (R2-C = O) 2O. 3. Process according to claim 1, characterized in that the acylation reagent in phase 1 is an acid chloride of. R2COCl formula. 4. Process according to any one of the preceding claims, characterized in that the acylation reagent, in step 1, is used in an amount at least stoichiometric with respect to the starting metaaminophenol (II), and preferably in an amount of at least 2 equivalents. 5. Process according to any one of the preceding claims, characterized in that the solvent for phase 1 consists of the same acylation reagent associated with the corresponding carboxylic acid. 6. Process according to any one of the preceding claims, characterized in that the catalyst used in phase · 2 is aluminum chloride A1C13. 7. Process according to any one of the preceding claims, characterized in that the selective reduction in step 3 is carried out by catalytic hydrogenation. 8. Process according to claim 7, characterized in that the hydrogenation catalyst consists of palladium carbon, preferably 5-10%, with a moisture content of the order of 50%. 9. Process according to any one of claims 7 and 8, characterized in that the hydrogenation is carried out in a protic solvent preferably selected from the lower alcohols, especially methanol, ethanol, monoglyme, monoisopropylglycol and 1 -methoxy-2-propanol. 10. Process according to claim 9, characterized in that the protic solvent is selected from methanol and ethanol. 11. Process according to any one of claims 7 to 10, characterized in that the hydrogen pressure is between 4 and 20 bar and is preferably of the order of 12 bar. 12. Process according to any one of claims 7 to 11, characterized in that the hydrogenation is carried out in the presence of an acid, preferably selected from phosphoric acid, sulfuric acid and acetic acid, according to a proportion of 0.5 to 2.5%. 13. Process according to any one of claims 7 to 12, characterized in that the reaction temperature is between 50 and 100 ° C, and is preferably 85 ° C. 14. Process according to any one of the preceding claims, characterized in that the hydroxyl function is O-substituted by means of an acid chloride R: C1. 15. Process according to any one of the preceding claims, characterized in that the R1 group is selected from the methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene, 3-phenylpropyl, p-methylbenzyl, p-chlorobenzyl, o-chlorobenzyl groups, or, p-dichlorobenzyl, p-nitrobenzyl, decyl, and more preferably still represents the benzyl group. 16. Process according to any one of the preceding claims, characterized in that the R2 group represents a C1-6 alkyl group, linear or branched, and is preferably selected from the methyl, ethyl, n-propyl, isopropyl, n-butyl groups , tert-butyl, pentyl, 1-ethylpropyl, hexyl, and more preferably still represents the n-propyl group. 17. Process according to any one of the preceding claims, characterized in that, when applied to the synthesis of 3- (benzyloxy) -4- (n-butyl) aniline (I '), it comprises the steps which consist of: 1) acylating the amino function and the hydroxyl function of the metaminophenol of formula (II) 'by means of butyric anhydride to form the compound of formula (III'), corresponding to compound (III) in which R2 represents the n-propyl group; 2) carrying out a Fries transposition reaction of the compound (III) obtained in the presence of aluminum chloride, to form the compound of formula (IV '), corresponding to the compound (IV) in which R2 is the n-propyl group; 3) carry out a selective catalytic hydrogenation in the presence of palladium carbon at 10% and with 50% humidity in methanol, in an acid medium, to obtain the compound of formula (V ') corresponding to the compound (V) in which R2 represents the n-propyl group; 4) reacting the resulting compound (V ') with benzyl chloride, then hydrolyzing the reaction mixture. 18. Process for preparing esters of 4-hydroxyquinolein-3-carboxylic acids, characterized in that it comprises the preparation of a disubstituted aniline (I) according to any one of claims 1 to 17.