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

“PROCESS FOR ISOLATION OF HALOSUBSITUTED HYDROXY BENZOIC ACID”

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 is related to a process for preparation of compound of formula I,

Formula I
wherein X is a halogen independently selected from chloro, bromo, and fluoro and n is 1-4.

BACKGROUND OF THE INVENTION
The present invention provides a process for preparation of halosubsituted hydroxy benzoic acid compounds, that are useful as intermediates in liquid crystal, recording material, pharmaceutical, and agriculture industry.
US6166246A discloses a process for preparation of 3,4-difluoro-2-hydroxybenzoic acid from 2,3,4-trifluorobenzoic acid using an alkali metal hydroxide in presence of 1,3-dimethyl-2-imidazolidinone at 150?.
CN102320960A and CN106336352A disclose a process for preparation of 6-fluorosalicylic acid from 2,6-difluorobenzonitrile using sodium hydroxide in water at 150-160? in low yield.
There is a need in the art to develop an economical and industrially applicable process for preparation of a compound of formula I.
The present invention providing an improved process for preparation of a compound of formula I to achieve high yield and selectivity with simple operations.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a process for preparation and isolation of a compound of formula I to achieve high yield and selectivity using simple operations, consuming less time.

SUMMARY OF THE INVENTION
In an aspect, the present invention discloses a process for preparation of a compound of formula I, comprising the steps of:

Formula I
wherein X is a halogen independently selected from chloro, bromo, and fluoro and n is 1-4.
a) reacting a compound of formula II with an aqueous base at 120-130? to obtain a reaction mixture;

Formula II
wherein X is a halogen independently selected from chloro, bromo, and fluoro and n is 1-4.
b) adding an organic solvent to the reaction mixture;
c) acidifying the reaction mixture using an acid to pH 1-2; and
d) isolating the compound of formula I.
In another aspect, the present invention provides a process for preparation of a compound of formula I, comprising the steps of:
a) reacting a compound of formula II with an aqueous base in a continuous flow reactor at 50-80? and collecting the reaction mass in an autoclave reactor;
b) heating the reaction mass of autoclave reactor to 125?;
c) adding an organic solvent to the reaction mass;
d) acidifying the reaction mixture using an acid to pH 1-2; and
e) isolating the compound of formula I.

DETAILS DECRIPTION OF THE INVENTION
The present invention provides a method for preparation of a compound of formula I.
The compound of formula I refers to a compound selected from group consisting of 2-fluoro-6-hydroxybenzoic acid; 2,4-difluoro-6-hydroxybenzoic acid; 2-chloro-6-hydroxybenzoic acid; 2,4-dichloro-6-hydroxybenzoic acid; 4-chloro-2-hydroxy benzoic acid; 4-fluoro-2-hydroxy benzoic acid; 4-chloro-2-fluoro-6-hydroxy benzoic acid and 3,4,6-trichloro-2-hydroxy benzoic acid or like.
As used herein, “continuous flow” refers to reaction of compound of formula II and aqueous base in a continuous flow reactor. The continuous flow reactor is made up of hastelloy or stainless steel.
In an embodiment, preferred compound of formula I is 2-fluoro-6-hydroxybenzoic acid; 2,4-difluoro-6-hydroxybenzoic acid and 4-fluoro-2-hydroxy benzoic acid.
The compound of formula II refers to a compound selected from 2,6-difluorobenzonitrile; 2,4,6-trifluorobenzonitrile; 2,4-difluorobenzonitrile; 2-chloro-6-fluoro-benzonitrile; 2,4-dichloro-6-fluorobenzonitrile; 4-chloro-2-fluorobenzonitrile; 4-chloro-2,6-difluorobenzonitrile and 3,4,6-trichloro-2-fluorobenzonitrile or like.
In an embodiment of the present invention, the process is carried in a metal reactor” selected from a group consisting of Hastelloy or stainless-steel reactor.
In an embodiment, reaction of a compound of formula II and an aqueous base is carried out in a hastelloy reactor at 110-150? and preferably at 120-130?.
The preferred base is sodium hydroxide and potassium hydroxide.
In an embodiment, the base is selected from sodium hydroxide or potassium hydroxide with concentration in the range from 20-50% and more preferably between 25-35% in aqueous solution. The molar ratio of aqueous base to the compound of formula II is in the range of 3-6.
In another embodiment, a process for preparation of a compound of formula I comprising, reacting a compound of formula II and aqueous base in a continuous flow reactor at 50-80? and collect the reaction mass in an autoclave reactor. It helps in completing reaction in less reaction hours.
The reaction may take 10-18 hours for continuous flow process and 20-24 hours in batch process of present invention.
The hydrolysis is carried out at a temperature range of 110-150?. It is observed that if the temperature is below 110? then reaction take long reaction hours of more than 40 hours to complete reaction and at temperature higher than 130?, the product gets decomposed, forming impurity such as halo substituted phenol.
In another embodiment, the addition of a base is followed by addition of an organic solvent selected from an ether or an ester selected from a group consisting of methyl tert-butyl ether, diethyl ether, diisopropyl ether or an ester selected from a group consisting of ethyl acetate and propyl acetate or the like.

The step of addition of an organic solvent is followed by acidification of the reaction mixture to a pH of 1-2 using an acid selected from a group consisting of hydrochloric acid and sulfuric acid or the like. Preferably, methyl tert-butyl ether is added followed by addition of 35-45% of hydrochloric acid to achieve pH of 1-2.
The process of isolation involves separating organic and aqueous phases of reaction mixture followed by concentrating organic phase to obtain slurry and filtering the reaction mass.
In another embodiment, the fluoride content of 0-10 ppm is achieved in the organic layer by washing the organic layer with water and brine.
In an embodiment, a compound of formula I may contain 0.005-3% of halo substituted phenol and 0.005-2% of halobenzene impurities.
In an embodiment, the compound of formula I is obtained with purity of 96 to 99.9% in a yield of 85-95%.
In an embodiment of the present invention, the process is carried out in absence of an organic solvent and catalyst.
In a preferred embodiment, a process for preparation of 2-fluoro-6-hydroxybenzoic acid comprising the steps of:
a) reacting 2,6-difluorobenzonitrile with 32-45% potassium hydroxide at 120-130? to obtain a reaction mixture;
b) adding a methyl-tert-butyl ether into the reaction mixture and cooling to a temperature of 10-25?;
c) acidifying the reaction mixture using hydrochloric acid to pH 1-2; and
d) isolating 2-fluoro-6-hydroxybenzoic acid.
In a preferred embodiment, a process for preparation of 2,4-difluoro-6-hydroxybenzoic acid comprising the steps of:
a) reacting 2,4,6-trifluorobenzonitrile with 32-45% potassium hydroxide at 120-130? to obtain a reaction mixture;
b) adding a methyl-tert-butyl ether into the reaction mixture and cooling to a temperature of10-25?;
c) acidifying the reaction mixture using hydrochloric acid to pH 1-2; and
d) isolating 2-fluoro-6-hydroxybenzoic acid.
The present invention also provides a process to carry out hydrolysis in a continuous flow reactor to obtain high selectivity of product in less reaction hours.
Unless stated to the contrary, any of the words “comprising”, “comprises” 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 completion of the reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure 5 liquid chromatography (UPLC), Gas chromatography (GC) and alike.
The following examples are 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-fluoro-6-hydroxy benzoic acid
An autoclave was charged with 2,6-difluoro benzonitrile (200 g, 1.44 moles) and potassium hydroxide solution (32%, 1386 g, 7.9 mole, 5.5 eq.). The reaction mass was slowly heated to 125°C and achieved pressure of 3-4 kg/cm2. The reaction mass was stirred for 24-26 hours and monitored for intermediate 2,6-difluorobenzoic acid, when the intermediate was below 5%, the reactor pressure was released into water then reaction mass was cooled down to room temperature. Methyl tert-butyl ether (800 g) was added to the reaction mass and cooled to 20°C. Then 35% hydrochloric acid was added to reaction mass to achieve pH 1-2 using the dropping funnel at temperature below 30°C throughout the acidification. After acidification, organic layer was separated and washed with water to remove fluoride. Once fluoride content reached less than 10 ppm, the organic layer was concentrated to obtain a slurry. Water (600 g) was charged in the slurry, concentrated the mass, and filtered. The product obtained was dried to obtain 2-fluoro-6-hydroxy benzoic acid (205 g).
Purity: 96%
Yield: 88%
Example 2: Preparation of 2-fluoro-6-hydroxy benzoic acid in continuous flow reactor
2,6-Difluoro benzonitrile (200 g, 1.44 moles) and potassium hydroxide solution (32%, 1386 g, 7.9 mole, 5.5 eq.) were charged in the vessels connected with a pump. The stainless steel reactor was heated to 60? and charged 2,6-difluoro benzonitrile and 32% potassium hydroxide from two input lines in the reactor. The output of reactor was collected in an autoclave reactor. Once, addition was completed, the autoclave was heated to 125? and stirred 10-15 hours at 3-4 kg /cm2 pressure. After reaction, methyl tert-butyl ether (800 g) was added to the reactor and cooled to 20°C. Then 35% hydrochloric acid was added to reaction mass to achieve pH 1-2 using the dropping funnel at temperature below 30°C throughout the acidification. After acidification, the organic layer was separated and washed with water to remove fluoride. Once fluoride content reached less than 10 ppm, the organic layer was concentrated to obtain slurry. Water (600 g) was charged in the slurry, concentrated the mass, and filtered. The product obtained was dried to obtain 2-fluoro-6-hydroxy benzoic acid (205 g).
Purity: 96.3%
Yield: 89%
Example 3: Preparation of 2-fluoro-6-hydroxy benzoic acid in continuous flow reactor
Difluorobenzonitrile (200 gm) and water (462 g) were added to a Hastelloy autoclave. The reaction mass heated to 90°C and potassium hydroxide (48%, 335 gm) was added to an autoclave through dip line (Vent open to atmosphere) while maintaining temperature below 95°C and stirred the reaction mass for 2 hours at 90°C. The progress of the reaction was monitored, after complete conversion, the reaction mass was heated to 125°C and charged remaining potassium hydroxide (48%, 589 gm) into autoclave. The reaction mass was stirred for 20 hours at 125°C. The reaction mas was cooled and added methyl tert-butyl ether (600gm), concentrated sulfuric acid (400 gm) through additional funnel by maintaining temperature below 25°C to achieve pH of 1-2. The reaction mixture was filtered, the aqueous layer was washed with methyl tert-butyl ether (400gm). The combined organic layer was washed with saturated sodium chloride solution. The organic layer was concentrated to obtain slurry. Water (600 gm) was added to the slurry and methyl tert-butyl ether is removed. Once vapour temperature reaches 95°C, the reaction mass cooled to room temperature and filtered. The filtered solid was dried and analysed.
Purity: 87.5%
Yield: 194 gm (86%)
,CLAIMS:WE CLAIM
1. A process for preparation of a compound of formula I, comprising the steps of:

Formula I
wherein X is a halogen independently selected from chloro, bromo, and fluoro and n is 1-4.
a) reacting a compound of formula II with an aqueous base at 120-130? to obtain a reaction mixture;

Formula II
wherein X is a halogen independently selected from chloro, bromo, and fluoro and n is 1-4.
b) adding an organic solvent to the reaction mixture;
c) acidifying the reaction mixture using an acid to pH 1-2; and
d) isolating the compound of formula I.
2. A process for preparation of a compound of formula I, comprising the steps of:
a) reacting a compound of formula II with an aqueous base in a continuous flow reactor at 50-80? and collecting the reaction mass in an autoclave reactor;
b) heating the reaction mass of autoclave reactor to 125?;
c) adding an organic solvent to the reaction mass;
d) acidifying the reaction mixture using an acid to pH 1-2; and
e) isolating the compound of formula I.
3. The process as claimed in claim 1 and claim 2, wherein the base is selected from sodium hydroxide and potassium hydroxide.
4. The process as claimed in claim 1 and claim 2, wherein the concentration of base is selected from 20-50%.
5. The process as claimed in claim 1 and claim 2, wherein the molar ratio of aqueous base to the compound of formula II is in the range of 3-6.
6. The process as claimed in claim 1 and claim 2, wherein the organic solvent is an ether selected from a group consisting of methyl tert-butyl ether, diethyl ether and diisopropyl ether or an ester selected from a group consisting of ethyl acetate and propyl acetate.
7. The process as claimed in claim 1 and claim 2, wherein the acid is selected from a group consisting of hydrochloric acid and sulfuric acid.

Dated this 17th day of August 2022.