Title of Invention

A METHOD OF PREPARING 4-ALKYL-3-ALKOXYANILINE

Abstract

The present invention relates to a method of preparing 4-alkyl-3- alkoxyaniline of in which R<SUP>1</SUP> represents a linear or branched C<SUB>1</SUB>-C<SUB>10</SUB> alkyl group or an aralkyl group in which the alkyl potion is linear and comprises from 1 to 4 carbon atoms and the aryl portion is phenyl, unsubstituted or substituted, in particular by one or more C<SUB>1</SUB>-C<SUB>3</SUB> alkyl groups or by several halogen atoms, or by one or more nitro radicals, and R<SUP>2</SUP> represents a linear or branched C<SUB>1</SUB>-C<SUB>16</SUB> alkyl group, from a compound of formula in which R<SUP>2</SUP> is as defined above and R<SUP>3</SUP> is the same as or different from R<SUP>2</SUP> and is a radical as described above with reference to R<SUP>2</SUP>, comprising the steps of: a)0-alkylating the free hydroxyl function of the compound of formula (IV) by reacting, in the presence of a base, with an alkylation agent, in a polar solvent as herein described, to produce an intermediate compound of formula (VI): b) reducing the carbonyl group and hydrolyzing the amide group of the intermediate compound of formula (VI) by reacting with hydrazine and a base in a polar solvent, and recovering the 4-alkyl-3 alkoxyaniline in a known manner. PRICE: THIRTY RUPEES

Full Text

DESCRIPTION The present invention relates to an improved method of preparing 4-alkyl-3-alkoxyaniline. Compounds such as 4-alkyl-3-alkoxyaniline are described extensively in the prior art; in fact, they constitute useful intermediates for the synthesis of esters of 4-hydroxyquinoline-3-carboxylic acids - amongst which is, for example, the methyl ester of 7-benzyloxy-6-butyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (methyl benzoquate) - which are used in the veterinary field owing to their coccidiostatic activity. International patent application W098/57921 describes a method for the synthesis of 4-alkyl-3-alkoxyaniline from meta-aminophenol, which can be represented by the following reaction scheme: In step I, the amine function is protected and the hydroxyl function of the meta-aminophenol is acylated with the same acylation reagent, which may be constituted by a carboxylic-acid chloride or anhydride. In step II, the phenolic ester (III) is rearranged by-heating in the presence of a Friedel-Crafts catalyst and thus bringing about a Fries rearrangement reaction; the reaction mixture is then hydrolyzed to give compound (IV). In step III, a selective reduction of the acyl group in position 4 of compound (IV) is performed; the selective reduction is performed by hydrogenation in the presence of an industrial catalyst, particularly palladium on carbon, with an H2 pressure of between 4 and 20 bar, in the presence of an acid, and in protic solvent. The compound (V) thus obtained is recovered in solid form by precipitation in water. Step IV consists of the O-substitution of the free hydroxyl group of compound (V) and deprotection of the amine function. For this purpose, a chloride of formula R^Cl in which the R1 group corresponds to the R1 group of the final compound desired is advantageously used. The object of the present invention is to provide an improved method for the synthesis of compounds of formula (I) which is advantageous and particularly economical in terms of plant and reagent costs. A subject of the present invention is therefore a method of preparing a 4-alkyl-3-alkoxyaniline compound of formula (I): in which R1 represents a linear or branched C1-C10 alkyl group or an aralkyl group in which the alkyl portion is linear and comprises from 1 to 3 carbon atoms and the aryl portion is phenyl, unsubstituted or substituted, in particular by one or more C1-C3 alkyl groups or by several halogen atoms, or by one or more nitro radicals, and R2 represents a linear or branched C1-C16 alkyl group, from a compound of formula (IV): in which R2 is as defined above and R3 is the same as or different from R2 and is a radical as described above with reference to R2, comprising the steps of: a) 0-alkylating the free hydroxyl function of the compound of formula (IV) by reaction, in the presence of a base, with an alkylation agent, in a polar solvent, thus producing an intermediate compound of formula {VI): b) reducing the carbonyl group and hydrolyzing the amide group of the intermediate compound of formula (VI) by reaction with hydrazine and a base in a polar solvent, thus producing the desired product of formula (I). The method according to the invention is based on the idea that, by performing the 0-alkylation reaction directly on compound (IV), it is possible to carry out the reduction reaction in the liquid phase with the use of hydrazine without the need to use expensive selective hydrogenation steps with the use of H2 and noble catalysts under pressure, thus achieving a substantial reduction in process and plant costs. In compound (IV) , the R^ and R^ groups may be the same or different and the compound is preferably prepared in accordance with the reactions of Steps I and II described in W098/57921 cited above. Steps a) and b) of the method according to the invention will now be described in greater detail. Step a: 0-alkylation of the free hydroxyl function of the compound of formula (IV) by means of an alkylation agent of formula R^A in which R^ is as defined above and A is a halogen atom, preferably a chlorine atom, to give an intermediate compound of formula (VI). In this step, the alkylation agent is reacted with the compound of formula (IV) in the presence of a base and in a polar solvent. The base is preferably selected from the group consisting of K2CO3, NasCOa, NaOH and KOH; the use of K2CO3 is most preferred. The polar solvent is preferably selected from the group consisting of dimethyl formamide (DMF), lower alcohols such as methanol and ethanol, glycols such as methyl glycol, 2-methoxy ethanol (methyl cellosolve), propylene glycol and ethylene glycol, and mixtures thereof. The use of DMF or of a mixture of lower alcohol and glycol is most preferred. The 0-alkylation reaction is preferably carried out at a temperature of between 50 and 80°C and is continued until the starting product is used up, which is determined by chromatographic separation, for example, by thin-layer chromatography (TLC) or high-pressure liquid chromatography (HPLC). The reaction time is preferably between 2 and 8 hours. Upon completion of the first step of the method, any salts present in the reaction mixture are removed by filtration or centrifuging; this step is necessary, in particular, if the 0-alkylation reaction was carried out in the presence of K2CO3 as the base. The subsequent reduction and hydrolysis reactions are preferably carried out in the same reactor as the O-alkylation without preliminary separation and recovery of the intermediate product (VI). Advantageously, if a glycol or a mixture of glycol and alcohol is used as solvent in the 0-alkylation step, the reduction reaction is preferably performed by the addition of the hydrazine reagent directly to the reaction mixture. Alternatively, if DMF (which constitutes a preferred solvent in terms of reaction yield) is used as solvent in the O-alkylation step a) , step b) (reduction) is preferably carried out after removal of the solvent from the reaction mixture, preferably by distillation. Step b: Reduction of the carbonyl group and hydrolysis of the amide group of the intermediate (VI) by reaction with hydrazine, thus producing the desired product (I). The reduction and hydrolysis reaction is carried out in a polar solvent and in the presence of a base. The solvent is preferably of the glycol type, such as propylene glycol, methyl cellosolve, or ethylene glycol, or is a lower alcohol such as methanol or ethanol, or is a mixture of these solvents. As mentioned above, the compound of formula (VI) produced in the previous step is dissolved in a polar solvent and a base such as KOH or NaOH is then added to the mixture thus obtained. In this step of the method, the use of ethylene glycol and KOH is preferred. After the addition of the base, a considerable increase in temperature takes place in the reaction mixture. When the temperature reaches a value of about 70 to 100°C, the hydrazine is added and the reaction mixture is left at this temperature for a period variable from 1 to 4 hours. The use of 80% hydrazine hydrate is preferred for this purpose. The excess hydrazine is then distilled at a temperature of 192-196°C, bringing the glycol to reflux. At this temperature, the reaction terminates within a maximum of 6 hours. The conclusion of the reaction may also be determined, for example, by TLC or HPLC in this step of the method. In a preferred embodiment of the above-described method, the starting compound of formula (IV) is 4-acetamido-2-hydroxy-butyrylphenone ("AcHBP", in which R2 and R3 are both methyl) and the alkylation reagent used in step a) is benzyl chloride. The reagents used in this step of the method are also preferably used in anhydrous form. The intermediate product of formula (VI) obtained upon completion of the benzylation reaction is therefore 4-acetamido-2-benzyloxybutyrylphenone ("BzAcHBP", in which R2 and R3 are both methyl and R1 is benzyl) , and the product of formula (I) obtained upon completion of the reduction and hydrolysis reaction is 3-benzyloxy-4-butylaniline ("BBA", in which R1 is benzyl and R2 is methyl) . This final product, which is poorly soluble in glycol, may be separated from the reaction mixture, for example, by extraction in toluene. For this purpose, the extraction is preferably carried out at a temperature of 70-80°C, by performing two successive extractions. The toluene phase is then evaporated at reduced pressure and the oil obtained (that is, the desired product) is distilled under vacuum. The purity of the product obtained can be evaluated, for example, by gas chromatography. The overall yield of the method according to the preferred embodiment described above, on a solids basis, is more than 80g of BBA produced per lOOg of AcHBP used. As mentioned above, the compounds of formula (I) are useful Intermediates for the preparation of derivatives of 4-hydroxyquinoline-3-carboxylic acids such as, for example methyl benzoquate. These derivatives are prepared from anilines of formula (I) by per se known methods. Patent application WO 98/57921 describes a method in which a substituted aniline is reacted with a dialkylalkoxy-alkylidene malonate compound to give a compound of the arylaminoalkylidene malonate type. Alternatively, the substituted aniline may be reacted with an alkyl malonate and an ester or an orthoester to give a compound of the arylaminoalkylidene malonate type, as described in International application WO99/11602. The arylaminoalkylidene malonate intermediate is then cyclized by heating as described, for example, in French patent FR 1487336. A second subject of the present invention is therefore a method of preparing a compound such as a 4-hydroxyquinoline-3-carboxylic acid ester of formula (X) or (X'): in which R1 and R2 are as defined above and R4 is a linear or branched C1-C4 alkyl group, in which' an intermediate of formula (I) , prepared according to the method of the present invention, is reacted with a dialkylalkoxyalkylidene malonate of formula (VII): in which R4 and R4 may be the same or different and represent, independently of one anotiher, an alkyl group as defined above with reference to R4, R6 represents a linear or branched C1-C4 alkyl, and R7 is a hydrogen atom, a linear or branched C1-C4 alkyl, or an aryl or aralkyl radical, and an ester or an orthoester of formula (IX) or (IX'), followed by a cyclization reaction by heating. According to a preferred embodiment of this method, the intermediate of formula (I) is 3-benzyloxy-4-butylaniline and the R4 group is methyl, and the compound of formula (X) or (X') obtained upon completion of the cyclization is the ester of 7-benzyloxy'-6-butyl-l, 4-dihydro-4-oxo-3-quinoline-carboxylic acid (methyl benzoquate). Accordingly the present invention provides a method of preparing 4-alkyl-3-alkoxyaniline of formula (I) in which R1 represents a linear or branched C1C10 alkyl group or an aralkyl group in which the alkyl potion is linear and comprises from 1 to 4 carbon atoms and the aryl portion is phenyl, unsubstituted or substituted, in particular by one or more C1-C3 alkyl groups or by several halogen atoms, or by one or more nitro radicals, and R2 represents a linear or branched C1-C16 alkyl group, from a compound of formula (IV): I I j (IV) in which R2 is as defined above and R3 is the same as or different from R2 and is a radical as described above with reference to R2 comprising the steps of: a) O-alkylating the free hydroxyl function of the compound of formula (IV) by reacting, in the presence of a base, with an alkylation agent, in a polar solvent as herein described, to produce an intermediate compound of formula (VI): b) reducing the carbonyl group and hydrolyzing the amide group of the intermediate compound of formula (VI) by reacting with hydrazine and a base in a polar solvent, and recovering the 4-alkyl-3 alkoxyaniline in a known manner. 12 DUPLICATE 'The following examples are provided by way of illustration and are not intended to limit the scope of the present invention in any way. EXAMPLES Example 1 100 g (0.452 moles) of AcHBP in 500 ml of glycol was loaded and 28 g of KOH flakes was then added. Heating to a temperature of between 50°C and 80°C was then started and 84 g (0.617 moles) of benzyl chloride was added dropwise over approximately 1 hour. The preselected temperature was maintained for a period of between 1 and 6 hours. The conclusion of the reaction was determined by TLC. Upon completion of the reaction, the mixture was cooled to a temperature of between 30 and 50°C and 205 g (4.1 moles) of KOH flakes was added. It was observed that the reaction was highly exothermic. The mixture was cooled to 50-80°C if necessary and hydrazine hydrate was added dropwise over a period of 1-3 hours; this temperature was maintained for 2-16 hours. When this period had elapsed, distillation was performed up to the reflux temperature of the glycol and the mixture was left at this temperature for 4-10 hours. When the necessary period had elapsed, the mixture was cooled to 70-100°c and 1500 ml of H2O was added with care, the mixture was stirred, and 300 ml of toluene was added. After the phases had been separated, the aqueous phase was extracted again with 500 ml of toluene. The organic phases were recombined and the toluene was evaporated under reduced pressure. A dark oil was obtained and was distilled under high vacuum to give 63-70 g of a yellow-coloured oil. Example 2 100 g (0.452 moles) of AcHBP in 4 00 ml of glycol was loaded and 108 g of anhydrous potassium carbonate was then added. Heating to a temperature of between 50°C and 80°C was then started and 84 g (0.617 moles) of benzyl chloride was added dropwise over approximately 1 hour. The preselected temperature was maintained for a period of between 1 and 6 hours. The conclusion of the reaction was determined by TLC. Upon completion of the reaction, the mixture was cooled to a temperature of between 30 and 50°C and the salts were filtered out. 205 g (4.1 moles) of KOH flakes was added to the solution thus obtained. It was observed that the reaction was highly exothermic. The mixture was cooled to 50-80°C if necessary and hydrazine hydrate was added dropwise over a period of 1-3 hours; this temperature was maintained for 2-16 hours. When this period had elapsed, distillation was performed up to the reflux temperature of the glycol and the mixture was left at this temperature for 4-10 hours. When the necessary period had elapsed, the mixture was cooled to 70-100°C and 15 00 ml of H2O was added with care, the mixture was stirred, and 3 00 ml of toluene was added. After the phases had been separated, the aqueous phase was extracted again with 500 ml of toluene. The organic phases were recombined and the toluene was evaporated at reduced pressure. A dark oil was obtained and was distilled under high vacuum to give 63-70 g of a yellow-coloured oil. Example 3 100 g (0.452 moles) of AcHBP in 500 ml of dimethyl formamide was loaded and 22 g of NaOH in pearl form was then added. Heating to a temperature of between 50°C and 80°C was then started and 84 g (0.617 moles) of benzyl chloride was added dropwise over approximately 1 hour. The preselected temperature was maintained for a period of between 1 and 4 hours. The conclusion of the reaction was determined by TLC. Upon completion of the reaction, the dimethyl formamide was evaporated at reduced pressure. 500 ml of glycol and 205 g (4.1 moles) of KOH flakes was added to the distillation residue. It was observed that the reaction was highly exothermic. The mixture was cooled to 50-80°C if necessary and hydrazine hydrate was added dropwise over a period of 1-3 hours; this temperature was maintained for 2-16 hours. When this period had elapsed, distillation was performed up to the reflux temperature of the glycol and the mixture was left at this temperature for 4-10 hours. When the necessary period had elapsed the mixture was cooled to 70-100°C and 1500 ml of H2O was added with care, the mixture was stirred and 3 00 ml of toluene was added. After the phases had been separated, the aqueous phase was extracted again with 500 ml of toluene. The organic phases were recombined and the toluene was evaporated at reduced pressure. A dark oil was obtained and was distilled under high vacuum to give 63-70 g of a yellow-coloured oil. Example 4 100 g (0.452 moles) of AcHBP in 500 ml of dimethyl formamide was loaded and 108 g of anhydrous potassium carbonate was then added. Heating to a temperature of between 50°C and 80oC was then started and 84 g (0.617 moles) of benzyl chloride was added dropwise over approximately 1 hour. The preselected temperature was maintained for a period of between 1 and 4 hours. The conclusion of the reaction was determined by TLC. Upon completion of the reaction, the dimethyl formamide was evaporated at reduced pressure. 500 ml of glycol and 140 g of NaOH in pearl form were added to the distillation residue. It was observed that the reaction was highly exothermic. The mixture was cooled to 50-80oC if necessary and hydrazine hydrate was added dropwise over a period of 1-3 hours; this temperature was maintained for 2-16 hours. When this period had elapsed, distillation was performed up to the reflux temperature of the glycol and the mixture was left at this temperature for 4-10 hours. When the necessary period had elapsed the mixture was cooled to 70-100°C and 1500 ml of H2O was added with care, the mixture was stirred and 3 00 ml of toluene was added. After the phases had been separated, the aqueous phase was extracted again with 500 ml of toluene. The organic phases were recombined and the toluene was evaporated at reduced pressure. A dark oil was obtained and was distilled under high vacuum to give 63-70 g of a yellow-coloured oil. Example 5 100 g (0.452 moles) of AcHBP in 300 ml of glycol and 200 ml of alcohol was loaded and 28 g of KOH flakes was then added. Heating to a temperature of between 50°C and 80°C was then started and 84 g (0.617 moles) of benzyl chloride was added dropwise over approximately 1 hour. The preselected temperature was maintained for a period of between 1 and 4 hours. The conclusion of the reaction was determined by TLC. Upon completion of the reaction, the mixture was cooled to a temperature of between 30 and 50°C and 2 05 g (4.1 moles) of KOH flakes, dissolved in 200 ml of glycol, was added. It was observed that the reaction was highly-exothermic. The mixture was cooled to 50-80°C if necessary and hydrazine hydrate was added dropwise over a period of 1-3 hours; this temperature was maintained for 2-16 hours. When this period had elapsed, distillation was performed up to the reflux temperature of the glycol and the mixture was left at this temperature for 4-10 hours. When the necessary period had elapsed, the mixture was cooled to 70-100°C and 1500 ml of H2O was added with care, the mixture was stirred, and 300 ml of toluene was added. After the phases had been separated, the aqueous phase was extracted again with 50 0 ml of toluene. The organic phases were recombined and the toluene was evaporated at reduced pressure. A dark oil was obtained and was distilled under high vacuum to give 63-70 g of a yellow-coloured oil. WE CLAIM: 1. A method of preparing 4-alkyI-3-alkoxyaniline of formula (I) in which R1 represents a linear or branched C1-C10 alkyl group or an aralkyl group in which the alkyl potion is linear and comprises from 1 to 4 carbon atoms and the aryl portion is phenyl, unsubstituted or substituted, in particular by one or more C1-C3 alkyl groups or by several halogen atoms, or by one or more nitro radicals, and R2 represents a linear or branched C1-C16 alkyl group, from a compound of formula (IV): in which R2 is as defined above and R3 is the same as or different from R2 and is a radical as described above with reference to R2, comprising the steps of: a) O-alkylating the free hydroxyl function of the compound of formula (IV) by reacting, in the presence of a base, with an alkylation agent, in a polar solvent as herein described, to produce an intermediate compound of formula (VI): b) reducing the carbonyl group and hydrolyzing the amide group of the intermediate compound of formula (VI) by reacting with hydrazine and a base in a polar solvent, and recovering the 4-alkyl-3 alkoxyaniline in a blown manner. 2. The method according to claim 1, in which the alkylation agent is a compound of formula R1A in which R1 is as defined above and A is a halogen atom, preferably a chlorine atom. 3. The method according to claim 1 or claim 2 in which the polar solvent of step a) is selected from the group consisting of dimethyl formamide, lower alcohols such as methanol and ethanol, glycols such as methyl glycol, 2-methoxy ethanol, propylene glycol, ethylene glycol, and mixtures thereof 4. The method according to any one of claims 1 to 3 in which the base of step a) is selected from the group consisting of NaOH, KOH, NA2CO3and K2CO3. 5. The method according to any one of the preceding claims in which, in step a) the polar solvent is dimethyl formamide and the base is K2CO3. 6. The method according to any one of the preceding claims in which the solvent of step b) is selected from the group consisting of glycols such as propylene glycol, 2-methoxy ethanol, ethylene glycol, lower alcohols such as methanol and ethanol, and mixtures thereof 7. The method according to any one of the preceding claims, in which the base of step b) is an alkali-metal hydroxide such as KOH or NaOH. 8. The method according to any one of the preceding claims in which, in step b), the base is KOH and the solvent is ethylene glycol. 9. The method according to any one of the preceding claims in which the reaction temperature in step a) is between 50 and 80°C. 10. The method according to any one of the preceding claims in which the reaction temperature in step b) is between 70 and 196°C. 11. The method according to any one of the preceding claims, in which R2 is methyl and the alkylation agent of step a) id benzyl chloride. 12. A method of preparing 4-alkyl-3- alkoxyaniline substantially as herein described and exemplified.

Documents:

0342-mas-2001 others.pdf

0342-mas-2001 abstract.jpg

0342-mas-2001 abstract.pdf

0342-mas-2001 claims.pdf

0342-mas-2001 correspondence others.pdf

0342-mas-2001 correspondence po.pdf

0342-mas-2001 description (complete).pdf

0342-mas-2001 form-1.pdf

0342-mas-2001 form-3.pdf

0342-mas-2001 form-5.pdf

0342-mas-2001 form-9.pdf