WO2003095417A1 - Process for the manufacture of 4-fluoro-anthranilic acid - Google Patents

Process for the manufacture of 4-fluoro-anthranilic acid Download PDF

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Publication number
WO2003095417A1
WO2003095417A1 PCT/IB2003/001772 IB0301772W WO03095417A1 WO 2003095417 A1 WO2003095417 A1 WO 2003095417A1 IB 0301772 W IB0301772 W IB 0301772W WO 03095417 A1 WO03095417 A1 WO 03095417A1
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process according
fluoro
formula
carried out
chloro
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PCT/IB2003/001772
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French (fr)
Inventor
Stefano Poli
Damiano Torrente
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Miteni S.P.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position

Definitions

  • the present invention concerns a process for preparing 4-fluoro- anthranilic acid (or 2-amino-4-fluorobenzoic acid). More precisely the invention concerns a new way of synthesis for preparing 4-fluoro-anthranilic acid through reaction passages, which may be easily industrialised, starting from an alkylic 3-chloro-4-fluoro-benzoate.
  • TECHNICAL BACKGROUND 4-fluoro-anthranilic acid is a compound widely used in synthesis chemistry, in particular as an intermediate in the preparation of pharmaceutical products (see for example U.S. Patent 4,833,270) or agrochemical products (see for example EP-A 360417).
  • the process of the invention also presents the advantage of being easy to achieve even on an industrial scale.
  • DETAILED DESCRIPTION OF THE INVENTION So, according to the first of its aspects, the invention concerns a process for preparing 4-fluoro-anthranilic acid of formula (I)
  • lower alkyl residue means, according to the invention, a straight or branched alkyl radical, having from 1 to 6 carbon atoms.
  • the nitration in step (a) can be carried out according to the processs well known to the skilled in the art; preferably, the nitration is carried out with a mixture of concentrated sulphuric acid and nitric acid, controlling the temperature below 80°C, advantageously below 30°C.
  • reaction product, compound (III) is obtained with excellent yields and with a high degree of purity and it is isolated according to the conventional techniques, for example by extraction with a suitable organic solvent, such as for example toluene or with a chlorinated solvent.
  • a suitable organic solvent such as for example toluene or with a chlorinated solvent.
  • the nitration of the ester, rather than of the acid chloride or of the acid per se, is novel and inventive above all when carried out in the experimental conditions of the preferred aspects of the invention.
  • the reaction in step (b) leads to the reduction of the nitro group into an amine group and to the simultaneous elimination of the chlorine atom.
  • This reduction is preferably carried out in a catalytic way, using for example a reducing agent such as hydrogen, in the presence of a suitable catalyst such as Pd/C.
  • a reducing agent such as hydrogen
  • a suitable catalyst such as Pd/C.
  • the hydrogenation may be carried out either in an autoclave at a suitable pressure or at atmospheric pressure.
  • reduction is carried out in an alcohol medium, for example in isopropyl alcohol, with Pd/C, at atmospheric pressure, and formic acid or ammonium formate in the presence of water, but other hydrogenation systems can also be used.
  • the reduction reaction is completed in a few hours and it can be followed by thin-layer chromatography (TLC) according to the practice well known to skilled in the art.
  • ester (IV) is obtained which is transformed into 4-fluoro-anthranilic acid (I) by simple hydrolysis using conventional techniques, for example in an acid or basic environment, or optionally in alcohol.
  • hydrolysis is carried out in a basic, alcohol medium, in the presence of an alkali metal hydroxide, for example sodium hydroxide, or with ammonium formate itself, used in excess, as a source both of hydrogen and of hydroxy ions.
  • an alkali metal hydroxide for example sodium hydroxide, or with ammonium formate itself, used in excess, as a source both of hydrogen and of hydroxy ions.
  • Steps (b) and (c) can be carried out after that without isolating the intermediate, depending on requirements; in practice the process of the invention can therefore be carried out without step (c) and go from compound (III) to compound (I) using an excess of base during the reduction in step (b).
  • the desired product (I) is then isolated as is usually done for amino acids, for example by precipitation, after having brought the pH of the reaction environment to about 4,5 by acid addition.
  • the end product (I) can be further purified, for example by chromatography or by crystallization in a suitable solvent, for example in ethyl acetate.
  • the process of the invention is therefore particularly effective for preparing 4-fluoro-anthranilic acid (I) starting from alkylic 3-chloro-4-fluoro- benzoate of formula (II), through the series of steps indicated above and with high yields.
  • the starting ester of formula (II) is prepared starting from a 3-chloro-4-fluoro-benzoil-halide of formula (V)
  • X represents halogen, by reaction with an lower aliphatic alcohol.
  • halogen designates, according to the present description, a halogen substituent; according to an advantageous aspect, the halogen is bromine of chlorine, the latter being preferred.
  • lower aliphatic alcohols designates, according to the present invention, straight or branched aliphatic alcohols containing from 1 to 6 carbon atoms, for example methanol, ethanol, isopropanol, n-butanol, etc., methanol and ethanol being particularly preferred alcohols.
  • the esterification reaction described above is a substantially exothermic one so it is not necessary to supply heat; more precisely, the mixing of alcohol with the benzoil-halide (V) leads to a spontaneous heating of the reaction mixture which approximately reaches the reflux temperature.
  • substantially anhydrous alcohols where the term "substantially anhydrous" means with low water content, preferably lower than 0.2 %, in order to avoid the formation of the corresponding acid.
  • an excess of alcohol generally an excess equal to a molar ratio benzoil-halide/alcohol of for example about 1/10, a ratio of about 1/2 being preferred for the correct performance of the reaction.
  • the yield of the esterification reaction is substantially quantitative and the compound (II) can be isolated for example by eliminating any excess alcohol, by distillation.
  • the alcohol may be metered indifferently into the benzoil-halide or the inverse process may be followed, bearing in mind that in the first case methyl chloride may be formed, as a sub-product, in a considerably lower quantity with respect to the second case.
  • the compound of formula (II) is methyl 3-chloro-4-fluoro-benzoate and it is obtained by esterification of 3-chloro-4-fluoro-benzoil-chloride, the latter being prepared by chlorination according to the process described in EP 903 334 in the name of the same applicant.
  • the starting product of formula (II) can otherwise be prepared by direct chlorination of an alkyl 4-fluoro-benzoate according to the process well known to skilled in the art, but with lower yields and selectivity.
  • the invention therefore concerns a process for the preparation of 4-fluoro-anthranilic acid of formula (I) which comprises reacting an ester of formula (II) as described in the passages from
  • the isopropanol solution (the crude product from the reduction reaction of the previous preparation) is put in a 250 ml round bottom flask, 2 eq of 20% soda are added and the solution is heated for 2 hours at 80°C (reflux). The alcohol is evaporated under reduced pressure.
  • the basic solution is first diluted with 50 cc of water then brought to pH about 4.5 with 37% HCI. A whitish precipitate is obtained which is filtered and dried at 60°C in a vacuum. 4.5 g of a pink solid are thus obtained, with a titre in 4-fluoro-anthranilic acid of 98% Glc.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention concerns a process for preparing 4-fluoro-anthranilic acid by nitration, reduction and hydrolysis of an alkyl 3-chloro-4-fluorobenzoate.

Description

"Process for the manufacture of 4-fluoro-anthranilic acid".
*************
FIELD OF THE INVENTION
The present invention concerns a process for preparing 4-fluoro- anthranilic acid (or 2-amino-4-fluorobenzoic acid). More precisely the invention concerns a new way of synthesis for preparing 4-fluoro-anthranilic acid through reaction passages, which may be easily industrialised, starting from an alkylic 3-chloro-4-fluoro-benzoate. TECHNICAL BACKGROUND 4-fluoro-anthranilic acid is a compound widely used in synthesis chemistry, in particular as an intermediate in the preparation of pharmaceutical products (see for example U.S. Patent 4,833,270) or agrochemical products (see for example EP-A 360417).
Several synthetic methods for preparing this acid have been proposed and described in the literature. The patents EP-551632, JP-05086000, JP-05058974, CS246350 and CS 246349 are cited as examples. SUMMARY OF THE INVENTION
It has now been found that it is possible to obtain 4-fluoro-anthranilic acid, with a high degree of purity and excellent yield, starting from an alkylic 3-chloro-4-fluoro-benzoate through an original process which contemplates few reaction passages.
The process of the invention also presents the advantage of being easy to achieve even on an industrial scale. DETAILED DESCRIPTION OF THE INVENTION So, according to the first of its aspects, the invention concerns a process for preparing 4-fluoro-anthranilic acid of formula (I)
Figure imgf000002_0001
which comprises
(a) performing a nitration on an alkylic ester of formula (II)
Figure imgf000003_0001
(ID wherein Alk represents an lower alkyl residue;
(b) reducing the compound (III) thus obtained
Figure imgf000003_0002
(Hi) to transform the nitro group into amine and eliminate the chlorine atom;
(c) hydrolysing the ester group of the compound (IV) thus obtained
Figure imgf000003_0003
and isolating the 4-fluoro-anthranilic acid of formula (I).
The term "lower alkyl residue means, according to the invention, a straight or branched alkyl radical, having from 1 to 6 carbon atoms.
The nitration in step (a) can be carried out according to the processs well known to the skilled in the art; preferably, the nitration is carried out with a mixture of concentrated sulphuric acid and nitric acid, controlling the temperature below 80°C, advantageously below 30°C.
The reaction product, compound (III) is obtained with excellent yields and with a high degree of purity and it is isolated according to the conventional techniques, for example by extraction with a suitable organic solvent, such as for example toluene or with a chlorinated solvent. The nitration of the ester, rather than of the acid chloride or of the acid per se, is novel and inventive above all when carried out in the experimental conditions of the preferred aspects of the invention. The reaction in step (b) leads to the reduction of the nitro group into an amine group and to the simultaneous elimination of the chlorine atom.
This reduction is preferably carried out in a catalytic way, using for example a reducing agent such as hydrogen, in the presence of a suitable catalyst such as Pd/C. The hydrogenation may be carried out either in an autoclave at a suitable pressure or at atmospheric pressure.
According to a preferred aspect of the invention, reduction is carried out in an alcohol medium, for example in isopropyl alcohol, with Pd/C, at atmospheric pressure, and formic acid or ammonium formate in the presence of water, but other hydrogenation systems can also be used. The reduction reaction is completed in a few hours and it can be followed by thin-layer chromatography (TLC) according to the practice well known to skilled in the art.
At the end of step (b) the ester (IV) is obtained which is transformed into 4-fluoro-anthranilic acid (I) by simple hydrolysis using conventional techniques, for example in an acid or basic environment, or optionally in alcohol.
Advantageously, hydrolysis is carried out in a basic, alcohol medium, in the presence of an alkali metal hydroxide, for example sodium hydroxide, or with ammonium formate itself, used in excess, as a source both of hydrogen and of hydroxy ions.
Steps (b) and (c) can be carried out after that without isolating the intermediate, depending on requirements; in practice the process of the invention can therefore be carried out without step (c) and go from compound (III) to compound (I) using an excess of base during the reduction in step (b). The desired product (I) is then isolated as is usually done for amino acids, for example by precipitation, after having brought the pH of the reaction environment to about 4,5 by acid addition.
In this way 4-fluoro-anthranilic acid is obtained with a purity higher than 95% calculated by means of gas-chromatography, usually with a purity higher than 97%. Optionally, the end product (I) can be further purified, for example by chromatography or by crystallization in a suitable solvent, for example in ethyl acetate.
The yield of the various passages of the process of the invention, in particular when carried out according to the aspects of the invention pointed out as particularly advantageous, is generally very high.
The significant increase in yield and selectivity and the possibility of scale up represent a second particularly advantageous aspect of the present invention and constitute an important innovation with respect to the processes of the prior art, in particular with respect to the process described in patent JP-05086000.
The process of the invention is therefore particularly effective for preparing 4-fluoro-anthranilic acid (I) starting from alkylic 3-chloro-4-fluoro- benzoate of formula (II), through the series of steps indicated above and with high yields. According to a preferred aspect of the invention, the starting ester of formula (II) is prepared starting from a 3-chloro-4-fluoro-benzoil-halide of formula (V)
Figure imgf000005_0001
wherein X represents halogen, by reaction with an lower aliphatic alcohol. The term "halogen" designates, according to the present description, a halogen substituent; according to an advantageous aspect, the halogen is bromine of chlorine, the latter being preferred. The expression "lower aliphatic alcohols" designates, according to the present invention, straight or branched aliphatic alcohols containing from 1 to 6 carbon atoms, for example methanol, ethanol, isopropanol, n-butanol, etc., methanol and ethanol being particularly preferred alcohols. The esterification reaction described above is a substantially exothermic one so it is not necessary to supply heat; more precisely, the mixing of alcohol with the benzoil-halide (V) leads to a spontaneous heating of the reaction mixture which approximately reaches the reflux temperature.
It is preferable to use substantially anhydrous alcohols, where the term "substantially anhydrous" means with low water content, preferably lower than 0.2 %, in order to avoid the formation of the corresponding acid.
Advantageously one operates with an excess of alcohol, generally an excess equal to a molar ratio benzoil-halide/alcohol of for example about 1/10, a ratio of about 1/2 being preferred for the correct performance of the reaction.
The yield of the esterification reaction is substantially quantitative and the compound (II) can be isolated for example by eliminating any excess alcohol, by distillation.
Alternatively one can operate in excess of benzoil-halide; in this case the non reacted benzoil-halide will have to be distilled, rather than the alcohol.
The alcohol may be metered indifferently into the benzoil-halide or the inverse process may be followed, bearing in mind that in the first case methyl chloride may be formed, as a sub-product, in a considerably lower quantity with respect to the second case.
According to a particularly preferred aspect of the present invention, the compound of formula (II) is methyl 3-chloro-4-fluoro-benzoate and it is obtained by esterification of 3-chloro-4-fluoro-benzoil-chloride, the latter being prepared by chlorination according to the process described in EP 903 334 in the name of the same applicant.
The starting product of formula (II) can otherwise be prepared by direct chlorination of an alkyl 4-fluoro-benzoate according to the process well known to skilled in the art, but with lower yields and selectivity.
According to another of its aspects the invention therefore concerns a process for the preparation of 4-fluoro-anthranilic acid of formula (I) which comprises reacting an ester of formula (II) as described in the passages from
(a) to (c) detailed above, in which said ester of formula (II) is obtained from a
3-chloro-4-fluoro-benzoil-halide of formula (V).
The compounds of formula (II) and (III) in which Alk is a methyl residue, that is methyl 3-chloro-4-fluoro-benzoate and methyl 5-chloro-4-fluoro-2-nitro- benzoate, have never been expressly described in the literature; they are therefore new compounds and represent a further aspect of the invention. The invention shall now be illustrated with experimental non limiting examples.
EXPERIMENTAL PART Example 1
Preparation of methyl 3-chloro-4-fluoro-benzoate
In a 250 ml four-necked round bottom flask, equipped with a mechanical stirrer, condenser and thermometer, 86.5 g of 3-chloro-4-fluoro-benzoic acid chloride are loaded and 28.1 g of anhydrous MeOH are added by a dosing funnel. The reaction is exothermic and spontaneously reaches 60°C. The methanol is metered keeping the temperature at about 60°. It is stirred for 1 hour then the excess methanol is distilled. In this way 80 g of yellow oil are obtained corresponding to the compound methyl 3-chloro-4-fluoro-benzoate.
Yield 97.29%. Example 2
Nitration process (step (a))
In a 250 ml four-necked round bottom flask, equipped with a mechanical stirrer, condenser and thermometer, 126 g of concentrated sulphuric acid are loaded, 80 g of methyl 3-chloro-4-fluoro-benzoate are added under stirring, the temperature is controlled with a water bath, 31 g of HNO3 are added slowly in 3-4 hours. The reaction is only moderately exothermic. At the end of metering, about 20% of the product is still not reacted, so it is left overnight under stirring at 25°C. 50 ml of methylene chloride are added, the organic phase is poured into ice, under stirring, then the 2 phases are separated, the organic phase is neutralised with 5% sodium bicarbonate, it is washed again and a liquid is obtained which, after evaporation of the solvent, becomes a pale yellow solid of 92 g corresponding to the compound methyl 5-chloro-4- fluoro-2-nitro-benzoate. Titre 89%, yield = 85.11% Example 3 Process by reduction and de-halogenation (step (b)) In a 250 ml round bottom flask, under a flow of nitrogen, 10g of methyl
5-chloro-4-fluoro-2-nitro-benzoate of the previous preparation are loaded, it is dissolved with 100 gr of isopropanol, and 5g of Pd/C 10%, 50% wet are added. The reaction mixture is heated to about 50°C. A solution of 24.24 g of ammonium formate in 24.24 g of water is prepared. The aqueous solution is metered slowly onto the alcohol solution in about 2 hours. It is then left under stirring for 1 hour, and left to cool. The end of the reaction is controlled with TLC. The Pd/C is filtered on paper, thus obtaining a pale yellow solution containing methyl 2-amino-4-fluoro-benzoate which turns brown in the air. Yield in solution 97.8% Example 4
Process of hydrolysis and precipitation from water (step (c))
The isopropanol solution (the crude product from the reduction reaction of the previous preparation) is put in a 250 ml round bottom flask, 2 eq of 20% soda are added and the solution is heated for 2 hours at 80°C (reflux). The alcohol is evaporated under reduced pressure. The basic solution is first diluted with 50 cc of water then brought to pH about 4.5 with 37% HCI. A whitish precipitate is obtained which is filtered and dried at 60°C in a vacuum. 4.5 g of a pink solid are thus obtained, with a titre in 4-fluoro-anthranilic acid of 98% Glc.

Claims

CLAIMS Process for preparing 4-fluoro-anthranilic acid of formula (I)
Figure imgf000009_0001
which comprises
(a) performing a nitration on the ester of formula (II)
Figure imgf000009_0002
(II) wherein Alk represents an lower alkyl residue; (b) reducing the compound (III)
Figure imgf000009_0003
(III) to transform the nitro group into amine and eliminate the chlorine atom; (c) hydrolysing the ester group of the compound (IV) thus obtained AIk
Figure imgf000009_0004
(IV) and isolating 4-fluoro-anthranilic acid of formula (I). Process according to claim 1 , wherein nitration in step (a) is carried out in a mixture of concentrated sulphuric acid and nitric acid, controlling the temperature below 80°C. 3. Process according to claim 2, wherein nitration in step (a) is carried out controlling the temperature below 30°C. 4. Process according to claim 1 , wherein reduction in step (b) is carried out in a catalytic way. 5. Process according to claim 4, wherein reduction in step (b) is carried out in an alcohol medium with Pd/C and formic acid or ammonium formate in the presence of water. 6. Process according to claim 1 , wherein hydrolysis in step (c) is carried out in a basic alcohol medium, in the presence of an alkali metal hydroxide. 7. Process according to claim 1 , wherein step (b) is carried out in the presence of an excess of base and step (c) is avoided. 8. Process according to any one of the previous claims wherein the ester of formula (II) is prepared starting from a 3-chloro-4-fluoro-benzoil- halide of formula (V)
Figure imgf000010_0001
(V) wherein X represents a halogen, by reaction with an lower aliphatic alcohol.
9. Process according to claim 8, wherein the lower aliphatic alcohol is chosen between methanol and ethanol.
10. Process according to claims 8 or 9, wherein X is a chlorine atom.
11. Process according to any one of the claims from 8 to 10, wherein the molar ratio between benzoil-halide of formula (V) and lower aliphatic alcohol is approximately equimolar.
12. Process according to any one of the previous claims wherein Alk is methyl. 13. Compound selected between methyl 3-chloro-4-fluoro-benzoate and methyl 5-chloro-4-fluoro-2-nitro-benzoate.
PCT/IB2003/001772 2002-05-09 2003-05-07 Process for the manufacture of 4-fluoro-anthranilic acid WO2003095417A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013015203A1 (en) * 2011-07-28 2013-01-31 日本軽金属株式会社 Isopropyl 3-chloro-4-methylbenzoate and method for producing same
CN113307740A (en) * 2021-05-27 2021-08-27 中瀚(齐河县)生物医药科技有限公司 Preparation method of 2-amino-4-fluorobenzoic acid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0586000A (en) * 1991-09-27 1993-04-06 Asahi Glass Co Ltd Production of 2-amino-4-fluorobenzoic acid
EP0647615A1 (en) * 1993-10-08 1995-04-12 Hoechst Aktiengesellschaft Process for the preparation of 5-fluoroanthranilic acid alkyl esters and or 5-fluoroanthranilic acid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0586000A (en) * 1991-09-27 1993-04-06 Asahi Glass Co Ltd Production of 2-amino-4-fluorobenzoic acid
EP0647615A1 (en) * 1993-10-08 1995-04-12 Hoechst Aktiengesellschaft Process for the preparation of 5-fluoroanthranilic acid alkyl esters and or 5-fluoroanthranilic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 0174, no. 13 (C - 1092) 3 August 1993 (1993-08-03) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013015203A1 (en) * 2011-07-28 2013-01-31 日本軽金属株式会社 Isopropyl 3-chloro-4-methylbenzoate and method for producing same
JP2013028559A (en) * 2011-07-28 2013-02-07 Nippon Light Metal Co Ltd Isopropyl 3-chloro-4-methylbenzoate and method for producing the same
CN113307740A (en) * 2021-05-27 2021-08-27 中瀚(齐河县)生物医药科技有限公司 Preparation method of 2-amino-4-fluorobenzoic acid

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