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 SALICYLIC ACIDS”

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

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for preparation of substituted salicylic acid.
BACKGROUNG OF THE INVNETION
The chemistry of substituted salicylic acids has been frequently studied with a view to prepare compounds of possible medicinal interest. Particularly halogenated salicylic acid is very useful as important intermediate in pharmaceutical industry.
Journal of Fluorine Chemistry (1982), 21(2), 191-199 provides a process for preparation of fluorosalicylic acid from salicylic acid by reaction with hydrogen fluoride. The hydrogen fluoride is hazardous gas to work with.
Synthetic Communications (2000), 30(3), 397-405 provides a preparation of 5-fluorosalicylic acid from 5-fluorosalicylaldehyde or 5-fluorosalicylic alcohol using silver nitrate and potassium hydroxide. The process involves large quantities of silver nitrate, carbon monoxide and dimethylamine.
European Journal of Organic Chemistry (2001), (15), 2911-2915 provides a process for preparation of 5-fluorosalicylic acid from 5-fluoro-2-(methoxymethyl)benzoic acid using boron trifluoride etherate complex in methanol.
Science of Synthesis (2007), 31a, 21-78 provides a preparation of 5-fluorosalicylic acid from salicylic acid via fluorination and gives a mixture of product.
Most of the process known for preparation of substituted salicylic acids involve either toxic, corrosive reagent or expensive reagent and catalyst.
Hence, there is a need in the art to develop a process for preparation of substituted salicylic acid. The present invention provides a simple process for preparation of substituted salicylic acids, which uses easily available reagents and avoids using expensive catalyst.

OBJECT OF THE INVENTION
The present invention provides a process for preparation of substituted salicylic acids using simple steps and easily available raw materials. The present invention process involves simple operation for isolation of product and do not generate toxic effluent, that need special disposal.

SUMMARY OF THE INVENTION
In an aspect, present invention provides a process for preparation of substituted salicylic acid, comprising the steps of:
a) diazotising and hydrolysing a substituted aniline using a nitrite and an acid in presence of water to obtain substituted phenol;
b) acylating the substituted phenol using an acylating agent and Lewis’s acid to form substituted hydroxyacetophenone;
c) methylating the substituted hydroxyacetophenone using a methylating agent to form substituted methoxyacetophenone;
d) oxidising the substituted methoxyacetophenone using an oxidising agent to form substituted methoxybenzoic acid; and
e) hydrolysing the substituted methoxybenzoic acid using an acid to form substituted salicylic acid.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “substituted” refers to one or more preferably up to 3 groups selected from halogen, hydroxy, alkoxy, alkyl, nitrile, carboxyl, nitro or the like. The alkyl may be selected from methyl, ethyl, and propyl or the like and halogen may be selected from chloro, bromo, iodo, and fluoro. The substituents may be present at any position selected from ortho, meta and para to aniline, provided that wherein n is greater than one, or two substituents may be present at both ortho-position to aniline.
As used herein, “substituted anilines” refers to a compound selected from halogenated aniline such as 2-chloroaniline , 2-fluoroaniline, 3-fluoroaniline, 3-chloroaniline, 4-fluoroaniline, 4-chloroaniline, 2,4-difluoroaniline or the like; alkylated aniline such as 2-methylaniline, 3-methylaniline, 4-methylaniline, 2-ethylaniline, 3-ethylaniline, 4-ethylaniline, 2,4-dimethylaniline, 2-chloro-4-methylaniline, 2-fluoro-4-methylaniline, 4-chloro-2-methylaniline, 4-fluoro-2-methylaniline or the like.
As used herein, “substituted phenols” refers to a compound selected from halogenated phenol such as 2-chlorophenol, 2-fluorophenol, 3-fluorophenol, 3-chlorophenol, 4-fluorophenol, 4-chlorophenol, 2,4-difluorophenol or the like; alkylated phenol such as 2-methylphenol, 3-methylphenol, 4-methylphenol, 2-ethylphenol, 3-ethylphenol, 4-ethylphenol, 2,4-dimethylphenol, 2-chloro-4-methylphenol, 2-fluoro-4-methylphenol, 4-chloro-2-methylphenol, 4-fluoro-2-methylphenol or the like.
As used herein, “substituted hydroxyacetophenones” particularly refers to “substituted o-hydroxyacetophenones” refers and selected from halogenated hydroxyacetophenones such as 3-chloro-2-hydroxyacetophenone, 3-fluoro-2-hydroxyacetophenone, 4-fluoro-2-hydroxyacetophenone, 4-chloro-2-hydroxyacetophenone, 5-fluoro-2- hydroxyacetophenone, 5-chloro-2-hydroxyacetophenone, 3,5-difluoro-2- hydroxyacetophenone or the like; alkylated hydroxyacetophenone such as 2-hydroxy-3-methylacetophenone, 2-hydroxy-4-methylacetophenone, 2-hydroxy-5-methylacetophenone, 3-ethyl-2-hydroxyacetophenone, 4-ethyl-2-hydroxyacetophenone, 5-ethyl-2-hydroxyactophenone, 2-hydroxy-3,5-dimethylacetophenone, 3-chloro-2-hydroxy-5-methylacetophenone, 3-fluoro-2-hydroxy-5-methylacetophenone, 5-chloro-2-hydroxy-3-methylacetophenone, 5-fluoro-2-hydroxy-3-methylacetophenone or the like.
As used herein, “substituted methoxyacetophenones” particularly refers to “substituted o-methoxyacetophenones” and selected from halogenated methoxyacetophenones such as 3-chloro-2-methoxyacetophenone, 3-fluoro-2-methoxyacetophenone, 4-fluoro-2-methoxyacetophenone, 4-chloro-2-methoxyacetophenone, 5-fluoro-2-methoxyacetophenone, 5-chloro-2-methoxyacetophenone, 3,5-difluoro-2-methoxyacetophenone or the like; alkylated methoxyacetophenones such as 2-methoxy-3-methylacetophenone, 2-methoxy-4-methylacetophenone, 2-methoxy-5-methylacetophenone, 3-ethyl-2-methoxyacetophenone, 4-ethyl-2-methoxyacetophenone, 5-ethyl-2-methoxyactophenone, 2-methoxy-3,5-dimethylacetophenone, 3-chloro-2-methoxy-5-methylacetophenone, 3-fluoro-2-methoxy-5-methylacetophenone, 5-chloro-2-methoxy-3-methylacetophenone, 5-fluoro-2-methoxy-3-methylacetophenone or the like.
As used herein, “substituted methoxybenzoic acids” particularly refers to “substituted 2-methoxybenzoic acids or substituted o-methoxybenzoic acids” and selected from halogenated methoxybenzoic acid such as 3-chloro-2-methoxybenzoic acid, 3-fluoro-2-methoxybenzoic acid, 4-fluoro-2-methoxybenzoic acid, 4-chloro-2-methoxybenzoic acid, 5-fluoro-2-methoxybenzoic acid, 5-chloro-2-methoxybenzoic acid, 3,5-difluoro-2-methoxybenzoic acid, or the like; alkylated methoxybenzoic acid such as 2-methoxy-3-methylbenzoic acid, 2-methoxy-4-methylbenzoic acid, 2-methoxy-5-methylbenzoic acid, 3-ethyl-2-methoxybenzoic acid, 4-ethyl-2-methoxybenzoic acid, 5-ethyl-2-methoxybenzoic acid, 2-methoxy-3,5-dimethylbenzoic acid, 3-chloro-2-methoxy-5-methylbenzoic acid, 3-fluoro-2-methoxy-5-methylbenzoic acid, 5-chloro-2-methoxy-3-methylbenzoic acid, 5-fluoro-2-methoxy-3-methylbenzoic acid or the like.
As used herein, “substituted salicylic acids” refers to a compound having “hydroxy” and “acid” group at ortho to each other and selected from halogenated salicylic acid such as 3-chlorosalicylic acid, 3-fluorosalicylic acid, 4-fluorosalicylic acid, 4-chlorosalicylic acid, 5-fluorosalicylic acid, 5-chlorosalicylic acid, 3,5-difluorosalicylic acid, or the like; alkylated salicylic acid such as 3-methylsalicylic acid, 4-methylsalicylic acid, 5-methylsalicylic acid, 3-ethylsalicylic acid, 4-ethylsalicylic acid, 5-ethylsalicylic acid, 3,5-dimethylsalicylic acid, 3-chloro-5-methylsalicylic acid, 3-fluoro-5-methylsalicylic acid, 5-chloro-3-methylsalicylic acid, 5-fluoro-3-methylsalicylic acid or the like.
In an embodiment, the present invention provides a process for preparation of substituted salicylic acid, comprising diazotising, and hydrolysing a substituted aniline using a nitrite and an acid in presence of water to obtain substituted phenol.
The nitrite may be selected from a group consisting of sodium nitrite, and potassium nitrite or the like, alkyl nitrite such as isoamyl nitrite, butyl nitrite, and tert-butyl nitrite or the like.
The acid used with nitrite may be selected from a group consisting of formic acid, acetic acid, propionic acid, butanoic acid, sulfuric acid, and phosphoric acid, or a mixture thereof. The molar ratio of a solvent to the substituted aniline is selected in the range from 2-10.
The diazotisation and hydrolysis step are carried out at a temperature in the range from -10 to 150?. The diazotisation is carried out at a temperature in the range of -10 to 10? and hydrolysis is carried out at a temperature in the range of 130-160?.
The molar of diazotising agent used in the present invention is in the range from 1-2 and preferably 1-1.1.
In an embodiment, the present invention provides a process for preparation of halogenated phenol, comprising a continuous step of diazotising and hydrolysing halogenated aniline using a nitrite in presence of acid and water to obtain halogenated phenol. The continuous process is carried out in a reactor selected from continuous stirred tank reactor (CSTR), and flow reactor or the like.
In another embodiment of the present invention, the step of diazotization and hydrolysis is carried out in continuous mode to form a diazonium salt solution and followed by its addition to an acid in presence of water in both continuous and simultaneous mode.
In an embodiment, the present invention provides a process for preparation of halogenated phenols from halogenated aniline, wherein the process is carried out in a flow reactor.
In an embodiment, the present invention provides a process for preparation of halogenated phenols, comprising a step of diazotising and hydrolysing halogenated anilines using sodium nitrite in presence of sulfuric acid and water to obtain halogenated phenols.
In an embodiment, the present invention provides a process for preparation of fluorinated phenol, comprising a step of diazotising and hydrolysing fluorinated aniline using sodium nitrite in presence of sulfuric acid and water to obtain fluorinated phenols.
In an embodiment, the present invention provides a process for preparation of alkylated phenol, comprising a step of diazotising and hydrolysing alkylated aniline using sodium nitrite in presence of sulfuric acid and water to obtain alkylated phenols.
In another embodiment of the present invention, the step of diazotisation and hydrolysis is carried out in a continuous mode, wherein an aqueous solution of sulphuric acid and 4-fluoroaniline are added into a flow reactor at 50-55? simultaneously, followed by addition of diazotization agent, followed by acid addition in presence of water to obtain 4-fluorophenol.
In another embodiment of the present invention, the step of diazotisation and hydrolysis is carried out in a continuous mode, wherein an aqueous solution of sulphuric acid and 4-chloroaniline are added into a flow reactor at 50-55? simultaneously, followed by addition of aqueous sodium nitrite, followed by sulfuric acid addition in presence of water to obtain 4-chlorophenol.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acid, comprising a step of acylating substituted phenol using an acylating agent and Lewis acid to obtain substituted hydroxyacetophenones.
The acylating agent may be selected from a group consisting of acetyl chloride, and acetic anhydride or the like and Lewis acid is selected from a group consisting of iron chloride, aluminium chloride, and zinc chloride or the like and a mixture thereof.
The step of addition of acylating agent is carried out at a temperature in the range from 5-20? and Lewis acid is added at a temperature in the range of 60-100?.
The molar of acylating agent used in the present invention is in the range from 1-2 and preferably 1-1.1.
The molar of Lewis acid used in the present invention is in the range from 1-4 and preferably 2-3.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acid, comprising a step of acylating substituted phenol using an acylating agent to form substituted phenyl acetate and reducing substituted phenyl acetate using Lewis acid to obtain substituted hydroxy acetophenone, wherein substituted phenyl acetate is used in-situ.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acid, comprising a step of acylating substituted phenol using an acylating agent and Lewis acid to obtain substituted hydroxyacetophenone, wherein substituted phenyl acetate is used in-situ.
In another embodiment, the step of acylating 4-fluorophenol using an acetyl chloride and aluminium chloride to form 5-fluoro-2-hydroxyacetophenone.
In another embodiment, the step of acylating 3-halogenated phenol using an acetyl chloride and aluminium chloride is carried out to obtain 4-halogenated-2-hydroxyacetophenone, wherein 6-halogenated-2-hydroxyacetophenone is very low in %age.
In another embodiment, the step of acylating 3-chlorophenol using an acetyl chloride and aluminium chloride is carried out to obtain 4-chloro-2-hydroxyacetophenone, wherein 6-chloro-2-hydroxyacetophenone is formed in an amount of less than 3%.
In another embodiment, the present invention provides a process for preparation of halogenated hydroxyacetophenone, comprising a step of acylating halogenated phenol using an acylating agent and Lewis acid.
In another embodiment, the present invention provides a process for preparation of fluorinated hydroxyacetophenone, comprising a step of acylating fluorinated phenol using an acylating agent and Lewis acid.
In another embodiment, the present invention provides a process for preparation of alkylated hydroxyacetophenone, comprising a step of acylating alkylated phenol using an acylating agent and Lewis acid.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acids, comprising a step of methylating the substituted hydroxyacetophenone using a methylating agent in presence of solvent to obtain substituted methoxyacetophenones.
The solvent is selected from a group consisting of water, and organic solvents such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, acetone, and tetrahydrofuran or the like.
The methylating agent may be selected from a group consisting of dimethyl sulfate, methyl iodide, methyl chloride, and sodium methyl sulfate or the like.
In another embodiment, the methylation is carried out a temperature in range of 20-70? and may be carried out under pressure conditions.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acid, comprising a step of methylating the substituted hydroxyacetophenone using a methylating agent in presence of base in a solvent to obtain substituted methoxyacetophenones.
The base is selected from a group consisting of carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate, or the like; bicarbonates such as sodium bicarbonate, potassium bicarbonate, hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide or the like. The base is used in solid form or pulverised form. The molar ratio of base is in the range from 0.5-3.5.
In another embodiment, the step of methylating substituted hydroxyacetophenone is carried out using dimethyl sulfate in presence of potassium carbonate to obtain substituted methoxyacetophenones.
In another embodiment, the present invention provides a process for preparation of halogenated methoxyacetophenones, comprising a step of methylating the halogenated hydroxyacetophenone using a methylating agent.
In another embodiment, the present invention provides a process for preparation of fluorinated methoxyacetophenones, comprising a step of methylating the halogenated hydroxyacetophenone using a methylating agent.
In another embodiment, the present invention provides a process for preparation of alkylated methoxyacetophenones, comprising a step of methylating the alkylated hydroxyacetophenone using a methylating agent.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acids, comprising a step of oxidising the substituted methoxyacetophenones using an oxidising agent to form substituted o-methoxybenzoic acids.
The oxidising agent may be selected from a group comprising of hypochlorites such as sodium hypochlorite, and potassium hypochlorite or the like, hypobromites such as sodium hypobromite, potassium hypobromite, and peroxides such as hydrogen peroxide or the like. The oxidising agent used in present invention are freshly prepared. The oxidising step is carried out at temperature in the range from 20-80?.
In another embodiment, the present invention provides a process for preparation of substituted salicylic acids, comprising a step of oxidising the substituted methoxy acetophenone using an oxidising agent to form substituted methoxybenzoic acids, wherein reaction is carried out in presence of solvent.
The oxidisation is carried out in a solvent selected from water, dimethyl sulfoxide, dimethyl formamide, acetonitrile, acetone, methyl tert-butyl ether, dimethyl ether, and ethyl methyl ether or the like.
In a preferred embodiment, the present invention provides a process for preparation of substituted salicylic acids, comprising the step of oxidising the substituted methoxyacetophenone using an oxidising agent in presence of water to obtain substituted methoxybenzoic acid.
In another embodiment, the present invention provides a process for preparation of halogenated o-methoxybenzoic acid, comprising a step of oxidising the halogenated o-methoxyacetophenone using an oxidising agent.
In another embodiment, the present invention provides a process for preparation of fluorinated o-methoxybenzoic acid, comprising a step of oxidising the fluorinated methoxyacetophenone using an oxidising agent.
In another embodiment, the present invention provides a process for preparation of alkylated o-methoxybenzoic acid, comprising a step of oxidising the alkylated methoxyacetophenone using an oxidising agent.
In another embodiment, present invention provides a process for preparation of substituted salicylic acid, comprising a step of hydrolysing substituted methoxybenzoic acid using an acid in presence of water.
The hydrolysis is carried out in an acid, wherein acid refers to an acid selected from a group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, propanoic acid, butanoic acid or the like and the mixture thereof. The acid may also be used in an aqueous form.
In another embodiment, the hydrolysis step is carried out in solvent, wherein solvent is an acid.
In another embodiment, the hydrolysis step is carried out in a mixture of acetic acid and aqueous hydrogen bromide.
The hydrolysis step to obtain substituted salicylic acid from substituted methoxybenzoic acid using an acid is carried out at a temperature in the range from 60-140?.
In another embodiment, the present invention provides a process for preparation of halogenated salicylic acid, comprising a step of hydrolysing the halogenated methoxybenzoic acid using an acid.
In another embodiment, the present invention provides a process for preparation of fluorinated salicylic acid, comprising a step of hydrolysing fluorinated methoxybenzoic acid using an acid.
In another embodiment, the present invention provides a process for preparation of alkylated salicylic acid, comprising a step of hydrolysing alkylated o-methoxybenzoic acid using an acid.
In an aspect, the present invention provides a process for preparation of 5-fluorosalicylic acid, comprising the steps of:
a) diazotising and hydrolysing 4-fluoroaniline using sodium nitrite and sulfuric acid in presence of water to obtain 4-fluorophenol;
b) acylating 4-fluorophenol using an acetyl chloride and aluminium chloride to form 5-fluoro-2-hydroxyacetophenone;
c) methylating the 5-fluoro-2-hydroxyacetophenone using a dimethylsulfate to form 5-fluoro-2-methoxyacetophenone;
d) oxidising the 5-fluoro-2-methoxyacetophenone using sodium hypobromite to form 5-fluoro-2-methoxybenzoic acids; and
e) hydrolysing the 5-fluoro-2-methoxybenzoic acids using aqueous hydrogen bromide and acetic acid to form 5-fluorosalicylic acid.
In an aspect, present invention provides a process for preparation of 4-chlorosalicylic acid, comprising the steps of:
a) diazotising and hydrolysing 3-chloroaniline using sodium nitrite and sulfuric acid in presence of water to obtain 3-chlorophenol;
b) acylating 3-chlorophenol using an acetyl chloride and aluminium chloride to form 4-chloro-2-hydroxyacetophenone;
c) methylating the 4-chloro-2-hydroxyacetophenone using a dimethylsulfate to form 4-chloro-2-methoxyacetophenone;
d) oxidising the 4-chloro-2-methoxyacetophenone using sodium hypobromite to form 4-chloro-2-methoxybenzoic acid; and
e) hydrolysing the 4-chloro-2-methoxybenzoic acid using aqueous hydrogen bromide and acetic acid to form 4-chlorosalicylic acid.
The isolation of product is carried out using extraction, filtration, precipitation, and distillation with column.
The extraction and crystallisation may be carried out using any solvent selected from chlorinated solvents such as dichloromethane, dichloroethane or the like, acetonitrile, acetone, ethers such as tetrahydrofuran, diethyl ether, dimethyl ether, or like and alkanes such as hexane, pentane, or the like and esters such as ethyl acetate or the like.
The compound of present invention may be isolated by any method selected from a group consisting of acidification, basification, neutralisation, extraction, filtration, solvent washing, boil-off, distillation, or combination thereof. The acid used for acidification may be selected from a group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butanoic acid, hydrochloric acid, sulfuric acid, ad phosphoric acid, or the mixture thereof.
The base used for basification may be used from a group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate or the like and their aqueous forms.
The neutralisation may be carried out using any base or acid selected from acid and base described herein.
In an embodiment, the present invention provides substituted salicylic acids of purity greater than 95% and preferably greater than 99%.
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 4-fluorophenol.
Water (500 g) and sulfuric acid (98.7 g) were charged in a reactor and 4-fluoroaniline was dropwise added in the reactor, while maintaining the temperature between 0-5°C, followed by addition of aqueous sodium nitrite solution at below 5?. The reaction was decomposed in aqueous sulphuric acid at 150?. The reaction mass was extracted and distilled to obtain product.
Purity: 89%, Yield: 81%
Example 2. Preparation of 4-fluorophenol in continuous flow reactor.
Water (15.0eq) and sulphuric acid (2.0eq, 98%) were charged into a continuous reactor and transferred to next reactor at 55?. The reaction mass was added with a stream of 4-fluoroaniline (1.0eq) to form a salt solution. The salt solution was transferred to next reactor and stirred at 55?. The reaction mass was transferred to next reactor at 30? and added a solution of sodium nitrite (1eq., 40%) in water to obtain diazonium salt solution. Then, diazonium salt solution reactor was added with a continuous flow of aqueous sulfuric acid in a preheated flow reactor at 138-140? at a constant rate. Collected the mass from product collection line of flow reactor and extracted with dichloromethane to get 4-fluorophenol.
Purity: 99%, Yield: 95%
Example 3. Preparation of 5-fluoro-2-hydroxyacetophenone.
4-Fluorophenol (100g) was charged in a reactor and cooled to 5°C and acetyl chloride (1.05eq) was slowly added into the reaction mass. The reaction mass was stirred for 3-4 hours and heated to 80-85°C. Aluminium chloride was added in lot wise portion. The reaction mass was treated with aqueous hydrochloric acid and extracted with dichloromethane. The product was isolated by crystallisation.
Purity: 99.2%, Yield: 90.5%
Example 4. Preparation of 5-fluoro-2-methoxyacetophenone.
5-Fluoro-2-hydroxyacetophenone (100g) and acetone (1000 ml) were charged in a reactor. Potassium carbonate was added in the reaction mass and heated the mass to 56-58°C. Then dimethyl sulphate (83 g) was added dropwise in the reaction mass and reaction mass was refluxed for 2-3 hours. After complete reaction, the reaction mass was filtered, and product was isolated by distillation. The crystallisation was carried out to isolate product.
Purity: 99.1%; Yield: 92%.
Example 5: Preparation of 5-fluoro-2-methoxyacetophenone.
5-Fluoro-2-hydroxyacetophenone (100g) and acetonitrile (1000 ml) were charged in a reactor. Potassium carbonate was added in the reaction mass and heated the mass to 56-58°C. Then dimethyl sulphate (83 g) was added dropwise in the reaction mass and refluxed the reaction mass for 2-3 hours. After complete reaction, the reaction mass was filtered, and product was isolated by distillation. The crystallisation was carried out to isolate product.
Purity- 99%; Yield: 91.7%.
Example 6. Preparation of 5-fluoro-2-methoxybenzoic acid
Preparation of Sodium hypobromite-
Water (1358 g) and sodium hydroxide (210 g) were added in a reactor, and cooled to 5-10°C. Then bromine (108 ml) was added dropwise into the reaction mixture for 2-3 hours.
5-Fluoro-2-methoxyacetophenone (100 g) was charged in a reactor and cooled to 5-10°C. Then, sodium hypobromite solution was added into the reaction mixture dropwise for 3-4 hours. After complete addition, reaction mass was heated to 50°C and reaction mass was maintained for 2-3 hours. After complete conversion, excess hypobromite was quenched with sodium bisulphite till pH-5-6. The product was isolated by extraction and neutralisation.
Purity: 99.1%; Yield: 91.8%
Example 7: Preparation of 5-fluoro-2-methoxybenzoic acid
Preparation of Sodium hypobromite-
Water (650g) and sodium hydroxide (100 g) were added in a reactor, and cooled to 5-10°C. Then bromine was added dropwise into the reaction mixture for 2-3 hours.
5-Fluoro-2-methoxyacetophenone (50 g) was charged in a reactor and cooled to 5°C. Then, sodium hypobromite solution was added dropwise for 3-4 hours. After complete addition, reaction mass was heated to 45°C and was maintained for 2-3 hours. After complete conversion, excess hypobromite was quenched with sodium bisulphite till pH-5-6.
Purity: 99%; Yield: 93%
Example 8. Preparation of 5-fluorosalicylic acid.
5-Fluoro-2-methoxybenzoic acid (100 g), acetic acid (1000 gm) and 30% aqueous hydrogen bromide (1000 g) were charged in a reactor and heated to reflux for 8-9 hours. After complete conversion, reaction mass was cooled at 5-10 °C to obtain the precipitate. The reaction mass was filtered and obtained solid was washed with chilled water and crystallized the product to get the pure mass.
Purity: 99%; Yield: 94%
Example 9: Preparation of 3-chlorophenol
Aqueous sulfuric acid (30%) was charged in a reactor and 3-Chloroaniline (1 equivalent) was added dropwise in the reactor, while maintaining the temperature between 0-5°C, followed by addition of aqueous sodium nitrite solution (40%) at below 5?. The reaction was decomposed in aqueous sulphuric acid at 150?. The reaction mass was extracted and distilled to obtain product.
Purity: 98.8%; Yield: 92%.
Example 10. Preparation of 4-chloro-2-hydroxyacetophenone
3-Chlorophenol (50 g) was charged in a reactor and cooled to 5°C and acetyl chloride (1.05eq) was slowly added into the reaction mass. The reaction mass was stirred for 3-4 hours and heated to 80-85°C. Aluminium chloride () was added into the reaction mass lot wise portion. The reaction mass was treated with aqueous hydrochloric acid and extracted with dichloromethane. The product was crystallised using n-hexane.
Purity: 99%; Yield: 90%.

Example 11. Preparation of 4-chloro-2-methoxyacetophenone
4-Chloro-2-hydroxyacetophenone (50 g) and acetone (500 ml) were charged in a reactor. Potassium carbonate was added in the reaction mass and heated to 56-58°C. Then dimethyl sulphate (1.1 eq.) was added dropwise in the reaction mass and reaction mass was refluxed for 2-3 hours. After complete reaction, the reaction mass was filtered, and product was isolated by distillation. The crystallisation was carried out to isolate product.
Purity: 98.1%; Yield: 92%.
Example 12. Preparation of 4-chloro-2-methoxybenzoic acid.
Preparation of Sodium hypobromite-
Water (450g) and sodium hydroxide (100 g) were added in a reactor, and cooled to 5-10°C. Then bromine was added dropwise into the reaction mixture for 2-3 hours.
4-Chloro-2-methoxyacetophenone (33 g) was charged in a reactor and cooled to 5-10°C. Then, sodium hypobromite solution was added dropwise into the reaction mass for 3-4 hours. After complete addition, reaction mass was heated to 50°C and was maintained for 2-3 hours. After complete conversion, excess hypobromite was quenched with sodium bisulphite till neutralisation. The reaction mass was extracted with dichloromethane and aqueous layer was cooled, acidified with concentrated hydrochloric acid to obtain the product.
Purity: 99.1 %; Yield: 90%
Example 13. Preparation of 4-chlorosalicylic acid.
4-Chloro-2-methoxybenzoic acid (25 g), acetic acid (250 g) and aqueous hydrogen bromide (30%, 250 g) were charged in a reactor and heated to reflux for 8-9 hours. After complete conversion, reaction mass was cooled at 5-10 °C to obtain the precipitate. The reaction mass was filtered and obtained solid was washed with chilled water and crystallized the product to get the pure mass.
Purity: 99%; Yield: 90%

,CLAIMS:WE CLAIM:
1. A process for preparation of substituted salicylic acid, comprising the steps of:
a) diazotising and hydrolysing a substituted aniline using a nitrite and an acid in presence of water to obtain substituted phenol;
b) acylating the substituted phenol using an acylating agent and Lewis’s acid to form substituted hydroxyacetophenone;
c) methylating the substituted hydroxyacetophenone using a methylating agent to form substituted methoxyacetophenone;
d) oxidising the substituted methoxyacetophenones using an oxidising agent to form substituted methoxybenzoic acid; and
e) hydrolysing the substituted methoxybenzoic acid using an acid to form substituted salicylic acid.
2. The process as claimed in claim 1, wherein the nitrite is selected from a group consisting of sodium nitrite, potassium nitrite, isoamyl nitrite, butyl nitrite, and tert-butyl nitrite.
3. The process as claimed in claim 1, wherein the acid used with nitrite is selected from a group consisting of formic acid, acetic acid, propionic acid, butanoic acid, sulfuric acid, and phosphoric acid, or a mixture thereof.
4. The process as claimed in claim 1, wherein the diazotisation and hydrolysis step are carried out at a temperature in the range from -10 to 150?.
5. The process as claimed in claim 1, wherein the acylating agent is selected from a group consisting of acetyl chloride, acetic anhydride and the Lewis acid is selected from a group consisting of iron chloride, aluminium chloride, and zinc chloride or a mixture thereof.
6. The process as claimed in claim 1, wherein the step of addition of acylating agent is carried out at a temperature in the range from 5-20? and Lewis acid is added at a temperature in the range of 60-100?.
7. The process as claimed in claim 1, wherein the methylating agent is selected from a group consisting of dimethyl sulfate, methyl iodide, methyl chloride, and sodium methyl sulfate.
8. The process as claimed in claim 1, wherein the methylation is carried out at a temperature in range of 20-70?.
9. The process as claimed in claim 1, wherein the oxidising agent is selected from a group comprising of sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, and hydrogen peroxide.
10. The process as claimed in claim 1, wherein the hydrolysis is carried out using an acid selected from a group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, propanoic acid, butanoic acid and the mixture thereof.

Dated 08th day of March 2024.