DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“A PROCESS FOR PREPARATION OF SUBSTITUTED BENZOIC ACIDS”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particular describe the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a process for preparation of chlorinated and fluorinated nitrobenzoic acid.
BACKGROUND OF INVENTION
The chlorinated and fluorinated nitrobenzoic acid of present invention are important intermediates in the pharmaceutical industry and find application as intermediate of albaconazole, which is an antifungal and a neuroprotectant.
PCT Application No. 1987007602 provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid by oxidising 2-chloro-4-fluorotoluene using potassium permanganate to obtain 2-chloro-4-fluorobenzoic acid followed by nitration to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid in 83% yield, using multiple purification steps.
PCT Application No. 2001083459 provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid from 2-chloro-4-fluorobenzoic acid in low yield of 58% using 90% nitric acid in presence of concentrated sulfuric acid.
Chinese Patent No. 106905161 provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid from 2-chloro-4-fluorobenzoic acid using concentrated sulfuric acid and fuming nitric acid in presence of a cobalt chloride and zirconium chloride catalyst.
Chinese Patent Application No. 113956148 provides an acid/photocatalytic oxidation reaction of carbon-hydrogen bonds at benzylic positions of aromatic compounds, using Bronsted acid in presence of light in 12-48 hours. Such long and slow processes are not feasible for industrial scales.
Hence, there is a need in the art to develop a process for preparation of chlorinated and fluorinated nitrobenzoic acid using simple operations and commercially viable procedures.
OBJECT OF THE INVENTION
The present invention provides an economical process for preparation of chlorinated and fluorinated nitrobenzoic acid.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of chlorinated and fluorinated nitrobenzoic acid, comprising the steps of:
a) chlorinating nitrotoluene to obtain chlorinated nitrotoluene;
b) reducing the chlorinated nitrotoluene to obtain chlorinated aminotoluene;
c) converting chlorinated aminotoluene to chlorinated fluorotoluene;
d) oxidizing chlorinated fluorotoluene to obtain chlorinated fluorobenzoic acid; and
e) nitrating chlorinated fluorobenzoic acid to obtain the chlorinated fluoronitrobenzoic acid.

DETAILED DESCRIPTION OF THE INVENTION
In an embodiment of the present invention, the chlorinated and fluoronitrobenzoic acid is selected from a group consisting of 2-chloro-4-fluoro-5-nitrobenzoic acid, 2,6-dichloro-4-fluoro-5-nitrobenzoic acid and 2-chloro-6-bromo-4-fluoro-5-nitrobenzoic acid or the like.
In another embodiment of the present invention, the chlorinated fluorobenzoic acid is selected from a group consisting of 2-chloro-4-fluorobenzoic acid, 2,6-dichloro-4-fluorobenzoic acid and 2-chloro-6-bromo-4-fluorobenzoic acid or the like.
In another embodiment of the present invention, the chlorinated fluorotoluene is selected from a group consisting of 2-chloro-4-fluorotoluene, 2,6-dichloro-4-fluorotoluene and 2-chloro-6-bromo-4-fluorotoluene or the like.
In another embodiment of the present invention, the chlorinated aminotoluene is selected from a group 2-chloro-4-aminotoluene, 2,6-dichloro-4-aminotoluene and 2-chloro-6-bromo-4-amonitoluene.
In another embodiment of the present invention, the chlorinated nitrotoluene is selected from a group 2-chloro-4-nitrotoluene, 2,6-dichloro-4-nitrotoluene and 2-chloro-6-bromo-4-nitrotoluene.
In an embodiment of the present invention, the step of chlorination is carried out using elemental chlorine in presence of catalytic amount of iodine in a solvent selected from a group consisting of dichloromethane, monochlorobenzene, chloroform, carbon tetrachloride and dichloroethane or the like.
In another embodiment of the present invention, the step of reduction is carried out using hydrogen in presence of a catalyst selected from a group consisting of raney nickel, palladium, platinum, nickel oxide, lindlar catalyst and palladium on carbon or the like in a molar ratio of 0.001-0.01.
In another embodiment of the present invention, the step of reduction is carried out in a solvent selected from a group consisting of methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, and 2-methyl-2-propanol or the like.
In another embodiment of the present invention, the step of reduction is carried out a temperature selected in the range from 60-100?.
In another embodiment of the present invention, the step of converting chlorinated aminotoluene to chlorinated fluorotoluene is carried out at a temperature of 0-30? using a diazotizing agent selected from a group consisting of sodium nitrites, potassium nitrites and nitrosyl sulfuric acid or the like followed by a step of decomposition.
In another embodiment of the present invention, the step of decomposition is carried out at a temperature of 50-90? using hydrogen fluoride. The step of decomposition is followed by neutralization using a base selected 5-12% of aqueous solution of sodium carbonate, sodium bicarbonate, potassium bicarbonate and sodium bicarbonate or sodium hydroxide or potassium hydroxide or the like.
In another embodiment of the present invention, the step of oxidation is carried out using oxygen in presence of manganese salts such as manganese oxide, manganese acetate, manganese acetylacetonate and cobalt salts such as cobalt oxide, cobalt acetate and cobalt acetylacetonate in a molar ratio of 0.001-0.01.
In another embodiment of the present invention, the step of oxidation is carried out using a mixture of cobalt acetate and manganese acetate in pure or tetrahydrate form.
In another embodiment of the present invention, the step of oxidation is carried out using a mixture of cobalt acetate and manganese acetate, in presence of an initiator selected from tert-butyl hydrogen peroxide, organic peracids and organic peroxyesters or the like. The step of oxidation is preferably carried out in presence of 70% of tert-butyl hydrogen peroxide.
In another embodiment of the present invention, the step of oxidation is carried out in presence of hydrobromic acid, and an organic acid selected from a group consisting of acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid and methane sulfonic acid or the like.
In another embodiment, the oxidation is carried out in presence an organic acid in a mass ratio 3 to 6 with respect to the corresponding toluene.
In another embodiment of the present invention, the oxidation is carried out at 100-180? and preferably 130-160? for 3-5 hours. After oxidation, reaction mass is quenched in ice cold water, filtered, and washed with water.
In another embodiment of the present invention, the step of nitration is carried out using a nitrating agent selected from a group consisting of nitric acid and nitrates such as potassium nitrate, sodium nitrate and copper nitrate, in presence of an acid is selected from a group consisting of glacial acetic acid, trichloroacetic acid, trifluoroacetic acid and phosphoric acid or concentrated sulfuric acid. In preferred embodiment, the nitrating agent is a 70% nitric acid.
In another embodiment of the present invention, the step of nitration is carried out a temperature selected in the range from 0-60?, using nitrating agent in a molar ratio of 1-2.0, preferably 1.0 -1.5.
In a specific embodiment, the present invention provides a process for preparation of a 2-chloro-4-fluoro-5-nitrobenzoic acid, comprising the steps of:
a) chlorinating 4-nitrotoluene with chlorine in presence of catalytic iodine and dichloromethane to obtain a 2-chloro-4-nitrotoluene;
b) reducing 2-chloro-4-nitrotoluene using hydrogen in presence of raney nickel in methanol to obtain 3-chloro-4-methylaniline;
c) diazotising 3-chloro-4-methylaniline with aqueous sodium nitrite and hydrogen fluoride and decomposing using hydrogen fluoride at 80? to obtain 2-chloro-4-fluorotoluene.
d) oxidising 2-chloro-4-fluorotoluene with oxygen and a catalytic mixture of manganese acetate and cobalt acetate, initiator and aqueous hydrobromic acid to obtain 2-chloro-4-fluorobenzoic acid; and
e) nitrating 2-chloro-4-fluorobenzoic acid using aqueous solution of nitric acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
EXAMPLE 1: Preparation of 2-chloro-4-nitrotoluene
4-Nitrotoluene (50g, 0.36moles) and iodine (1wt.% w.r.t 4-nitro toluene) were charged into a reactor. The chlorine gas (31g, 0.44moles) was purged into it at 70-80?. The progress of the reaction mass was monitored by gas chromatography. After achieving the desired conversion, the reaction mass was cooled to 35-40oC and dichloromethane (100g, 1.2moles) was added. The sodium bisulphite aqueous solution (10%, 3.6g, 0.035mole) was added to neutralise the reaction mixture. The layers were separated, and the titled compound was isolated by evaporating the solvent (Purity 98.3%, Yield 95%).

EXAMPLE 2: Preparation of 3-chloro-4-methylaniline
2-Chloro-4-nitrotoluene (50g, 0.29moles) in methanol (480g, 15.0moles) and 50% raney nickel (0.17g, 0.0015moles) were charged in a reactor under nitrogen atmosphere. The reaction mass was heated to 90? and pressure was raised to 16 bar by addition of hydrogen gas (1.75g, 0.88moles). The progress of the reaction was monitored by gas chromatography. After getting the desired conversion, the reaction mass was cooled and unload under nitrogen atmosphere. The reaction mass was distilled out to isolate the titled compound (Purity 98.6, Yield 91.0%).

EXAMPLE 3: Preparation of 3-chloro-4-methylaniline
2-Chloro-4-nitrotoluene (50g, 0.29moles) in methanol (480g, 15.0moles) and 5% Pd/C (0.25g, 0.00012moles) were charged in a reactor under nitrogen atmosphere. The reaction mass was heated to 60? and pressure was raised to 14-16bar by addition of hydrogen gas (1.75g, 0.88moles). The progress of the reaction was monitored by gas chromatography. After getting the desired conversion, the reaction mass was cooled and unloaded under nitrogen atmosphere. The reaction mass was filtered, and the filtrate was distilled out to isolate the titled compound (37.13g, Purity 97.6, Yield 90.0%).

EXAMPLE 4: Preparation of 2-chloro-4-fluorotoluene
Hydrogen fluoride (74g, 3.71moles) was charged in a HAST-C reactor (250 mL) maintained at 0? and equipped with condenser. Charged 3-chloro-4-methylaniline (35g, 0.25moles) dropwise into reactor at 5 to 10?. Then, sodium nitrite (18g, 0.26 moles) was charged lot-wise into the reaction mass while maintaining the temperature between 5 to 10? and gradually stirred at a temperature of 70 to 80? for additional 2 hours. The reaction mass was cooled down to 5-10 ? and layers were separated. The organic layer was neutralized by using 8-10% base (0.35moles). The neutralized organic layer was distilled to titled compound (Purity: 99.2, Yield: 80%).

EXAMPLE 5: Preparation of 2-chloro-4-fluorobenzoic acid
Cobalt acetate tetrahydrate (0.13g, 0.0005moles), manganese acetate tetra hydrate (0.12g, 0.0005moles), 70% tert-butyl hydroperoxide (0.23g, 0.0018moles), 48% hydrobromic acid solution (0.29g, 0.0017moles) and acetic acid (110g, 1.82moles) were charged in an autoclave. 2-Chloro-4-fluorotoluene (25g, 0.17moles) was added into the reactor and agitation was started. The pressure of reaction mass was raised 18-21bar using oxygen gas. Heated the reaction mass to 160? and maintained for 3 hours. After desired conversion, the reaction mass was quenched into ice water (115 g, 6.4 moles), stirred for 30 minutes, and filtered to obtain solid. Washed the obtained solid with water thrice (4*40 g, 8.89 moles) and dried at 60? under vacuum to obtain titled compound (Purity: 98.5, Yield 85.1%).

EXAMPLE 6: Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid
Sulfuric acid (186g, 1.86moles) and 2-chloro-4-fluorobenzoic acid (25g, 0.14 moles) were charged into the reactor and cooled to 0? under stirring. Charged dropwise 65% nitric acid (20g, 0.21moles) into the reaction mass at 0 to 5?. The reaction mas was heated to 50-55oC for 3 hours. After desired conversion, quenched the reaction mass into ice water (250g, 13.8moles), stirred for 30 minutes and filtered. Washed the obtained solid with water, dried at 60oC for 8-10hrs to get titled compound (Purity: 99.1; Yield:75% ).

,CLAIMS:

WE CLAIM
1. A process for preparation of chlorinated and fluorinated nitrobenzoic acid, comprising the steps of:
a) chlorinating nitrotoluene to obtain chlorinated nitrotoluene;
b) reducing the chlorinated nitrotoluene to obtain chlorinated aminotoluene;
c) converting the chlorinated aminotoluene to chlorinated fluorotoluene;
d) oxidizing chlorinated fluorotoluene to obtain chlorinated fluorobenzoic acid; and
e) nitrating the chlorinated fluorobenzoic acid to obtain chlorinated fluoronitrobenzoic acid.
2. The process as claimed in claim 1, wherein the step of chlorination is carried out using elemental chlorine in presence of a catalytic amount of iodine in a solvent selected from a group consisting of dichloromethane, monochlorobenzene, chloroform, carbon tetrachloride and dichloroethane.
3. The process as claimed in claim 1, wherein the step of reduction is carried out using hydrogen in presence of a catalyst selected from a group consisting of raney nickel, palladium, platinum, nickel oxide, lindlar catalyst and palladium on carbon.
4. The process as claimed in claim 1, wherein the step of reduction is carried out in a solvent selected from a group consisting of methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, and 2-methyl-2-propanol.
5. The process as claimed in claim 1, wherein the step of reduction is carried out at a temperature selected in the range from 60-100?.
6. The process as claimed in claim 1, wherein the step of oxidation is carried out using a mixture of cobalt acetate and manganese acetate, in presence of an initiator selected from tert-butyl hydrogen peroxide, organic peracids and organic peroxyesters.
7. The process as claimed in claim 1, wherein the step of oxidation is carried out at a temperature range of 100-180?.
8. The process as claimed in claim 1, wherein the step of oxidation is carried out in presence of hydrobromic acid, and an organic acid selected from a group consisting of acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid and methane sulfonic acid.
9. The process as claimed in claim 1, wherein the step of nitration is carried out using a nitrating agent selected from a group consisting of nitric acid and nitrates selected from potassium nitrate, sodium nitrate and copper nitrate.
10. The process as claimed in claim 1, wherein the step of nitration is carried out a temperature selected in the range from 0-60?.
Dated this 20th day of December 2022.