FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
THE PATENTS RULES, 2006
COMPLETE
Specification
(See Section 10 and Rule 13)
A PROCESS FOR THE PREPARATION OF ALKOXY BENZOIC ACID
GHARDA KEKI HORMUSJI
an Indian National
of GHARDA HOUSE, 48 HILL ROAD,
BANDRA (WEST), MUMBAI 400 050, INDIA. MAHARASHTRA, INDIA

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

Field of Disclosure
The present disclosure relates to an etherification process.
The disclosure particularly relates to a process to prepare alkoxy derivatives
of hydroxy benzoic acid which are useful chemical intermediates.
Background
Alkoxy benzoic Acid products find use as intermediates for pharmaceutical products, in agro chemicals, in dyes, fragrances, and as adhesive components. o-Methoxybenzoic acid or anisic acid, is a useful raw material for pharmaceutical agents, agricultural chemicals, dyes, fragrances etc. 2-Ethoxybenzoic acid is used as a component in some dental cement.
There are various methods known in art for preparation of alkoxy benzoic acids. General method of etherification of Phenols is by using alcohols and strong mineral acids as catalysts, however the reactions are carried out at high temperatures and yields are generally low due to residual tar formation.
Etherification of salicylic acid to produce o-anisic acid is also carried out using reagents like methyl iodide or methyl bromide, however the reagents are very costly. Also o-anisic acid so produced contains lot of unreacted salicylic acid which is not easily removed.
IN247718 discloses an etherification process of para Hydroxy Benzoic Acid (para-salicylic acid) using Dimethyl Sulfate in the presence of Quaternary ammonium salt.

IN225931 relates to a process of preparation of 2 Ethoxy Benzoic Acid by reacting Salicylic Acid with diethyl sulphate and a quaternary ammonium salt in the presence of an alkali hydroxide solution.
US2003045748 discloses the process for preparing ethers of hydroxybenzoic acids using an alkyl halide and a base.
However in all the above processes, the reactants are costly or the reaction time is very high or the product mixture contains large amount of salicylic acid. Unconverted hydroxy benzoic acid is difficult to remove from the product mixture.
To obviate the drawbacks associated with the prior art, there is felt a need to develop a feasible process for preparing o-anisic acid.
Objects of the Invention
The main object of the present invention is to provide a commercially feasible process for preparing alkoxy benzoic acid.
Another object of the present invention is to provide a process for preparing alkoxy benzoic acid containing minimum amount of impurity.

Summary of the Invention
In accordance with the present invention, there is provided a process for preparing alkoxy benzoic acid of formula (I), said process comprising the following steps of:
a) reacting a salt of hydroxy benzoic acid of formula (II) with an alkylating agent, in the presence of a polar aprotic solvent ,at a temperature in the range 25°C to 100°C and at a pressure in the range of 4- 10 kg/cm2, to form a product mixture containing alkoxy alkyl benzoate of formula (III);

b) removing the solvent from the product mixture to yield crude alkoxy alkyl benzoate of formula (III);
c) hydrolyzing the crude alkoxy alkyl benzoate of formula (III)at a pH in the range of 8-14 to yield a salt of an alkoxy benzoic acid of formula (IV) ; and
d) acidifying the alkoxy salt of benzoic acid to obtain ortho-alkoxy benzoic acid of formula (I).

Typically, the polar aprotic solvent is selected from the group consisting of dimethyl acetamide (DMAc), N-methylpyrrolidinone (NMP), sulfolane, acetonitrile, dimethylsulfoxide and dimethyl formamide.
Typically, the polar aprotic solvent is dimethylformamide.
Typically, the amount of polar aprotic solvent used is in the range of 5 to 15 times v/w of the salicylate salt.
Typically, the alkylating agent is an alkyl halide selected from the group consisting of methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl and butyl halide.
In a preferred embodiment of the present invention, the alkylating agent is methyl chloride gas.
Typically, the hydroxy benzoic salt of formula (II) is disodium salt of salicylic acid.
Typically, the amount of methyl chloride is 1 to 4 moles per mole of disodium salt of salicylic acid.
Typically, the alkoxy benzoic acid of formula (I) is ortho-methoxy benzoic acid.

Brief Description of the Accompanying Drawing
Figure 1 illustrates the reaction scheme for preparing o-anisic acid from disodium salt of Salicylic acid.
Detailed description of the Invention
The present invention provides a process for preparing ether derivatives of hydroxy benzoic acid using alkyl chloride.
Some of the important ether derivatives of hydroxy benzoic acid are O-Methoxybenzoic acid/ anisic acid and 2-Ethoxybenzoic acid. O-Methoxybenzoic acid is a useful raw material for pharmaceutical agents, agricultural chemicals, dyes, fragrances etc and 2-Ethoxybenzoic acid is used as a component in some dental cement.
In accordance with the present invention, hydroxy benzoic acid is converted to a disodium salt (of formula II) using sodium hydroxide solution and the water formed during the process is removed by azeotropic distillation using xylene. The disodium salt so formed is filtered and dried. Etherification of disodium salt derivative is carried out using alkyl chloride, various alkyl chlorides such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl and butyl halide can be used.
In a preferred embodiment of the present invention, the etherification reaction is carried out in anhydrous condition to ensure complete reaction. The reaction is carried out in polar aprotic solvent such as dimethyl

acetamide (DMAc), N-methylpyrrolidinone (NMP), sulfolane, acetonitrile, dimethylsulfoxide and dimethyl formamide. The alkoxy alkyl benzoate (of formula III) so obtained is then hydrolyzed to compound of formula (IV) which is then acidified to yield alkoxy benzoic acid of formula (I).

Formula (IV)
In a preferred embodiment of the present invention, the disodium salt of salicylic acid is treated with an anhydrous alkyl chloride (having less than 0.1% moisture) selected from the group consisting of methyl chloride and ethyl chloride , in the presence of polar aprotic solvent selected from the group consisting of dimethyl acetamide (DMAc), N-Methylpyrrolidinone (NMP), sulfolane, acetonitrile, dimethylsulfoxide and dimethyl formamide. The amount of polar aprotic solvent used is in the range of 5 to 15 times v/w of the salicylate salt. The reaction is carried out in an autoclave at a temperature in the range 25°C to 100°C and at a pressure in the range of 4-

'-t
10 kg/cm . Excess alkyl chloride is used to ensure complete conversion of salicylate salt to alkyl ester of salicylate (dialkyl salicylate), 3-4 molar excess of alkyl chloride is used. After completion of reaction, solvent is removed from the product mixture by vacuum distillation and the residue of dialkyl salicylate is hydrolyzed by refluxing in 2.5 N sodium hydroxide solution to yield sodium salt of ortho-alkoxy benzoic acid. The hydrolyzed mixture is then extracted with a suitable solvent to remove any unhydrolyzed alkyl ester and then further acidified with a mineral acid to yield more than 80% ortho-alkoxy benzoic acid with purity more than 99%. Unconverted salicylic acid is less than 0.5%
The invention is further illustrated with the help of examples which do not limit the scope of the invention.
Example 1
In a pressure autoclave was charged lmole of Disodium salt of salicylic acid, 500 ml DMF [Kf < 0.1%]. 168.5 gm of Methyl chloride gas was passed into the mixture at 30° over 0.5 hr to have 4 kg/cm2 pressure. Temp of the reaction mass increased to 50° due to exothermicity. Reaction mass heated further to 90°C & maintained for 10 hrs. Reaction pressure during the maintenance decreased from 7 kg/cm2 to 3.5 kg/cm2. After the completion of reaction, DMF was removed under reduced pressure to obtain a concentrated mass containing Anisic ester. The Anisic ester was then hydrolyzed by heating the concentrated mixture with aqueous alkaline solution for 1 hr and then acidified to crystallize out ortho-anisic acid which was filtered and dried (127 gms). HPLC of the anisic acid so obtained

showed purity of 96.66 % with 0.4% Salicylic acid. Overall yield of ortho-anisic acid obtained was 87%.
Example 2
In a pressure autoclave was charged 1mole of Disodium salt of salicylic acid, 450 ml NMP [Kf < 0.1%]. 177 gm of Methyl chloride gas was passed in to the mixture at 30°& as in example 1. reaction mass heated further to 90°C & 7 kg pressure for 9 hrs. After the reaction, NMP was removed under reduced pressure to obtain a concentrated mass containing Anisic ester. The Anisic ester was then hydrolyzed by heating the concentrated mixture with aqueous alkaline solution for 1 hr and then acidified to crystallize out ortho-anisic acid which was filtered and dried (125 gms). HPLC of the anisic acid so obtained showed purity of 97.25 % Anisic acid with 0.3 % Salicylic acid. Overall yield of ortho-Anisic acid obtained was 86 %.
Example 3
In a pressure autoclave was charged lmole of Disodium salt of salicylic acid, 600 ml DMF [Kf < 0.1%]. 194 gm of ethyl chloride gas was passed into the mixture at 30° over 0.5 hr to have 3.5 kg/cm2 pressure. Temp of the reaction mass increased to 45° due to exothermicity. Reaction mass heated further to 90°C & maintained for 10 hrs. Reaction pressure during the maintenance decreased to 3 kg/cm2 from 6.5 kg/cm2. After the completion of reaction, DMF was removed under reduced pressure to obtain a concentrated mass containing 2-ethoxy benzoic acid ester. The ester was

then hydrolyzed by heating the concentrated mixture with aqueous alkaline solution for 1 hr and then acidified to crystallize out 2-ethoxy benzoic acid which was filtered and dried (150 gms). HPLC of the 2-ethoxy benzoic acid so obtained showed purity of 97.02 % with 0.5% Salicylic acid. Overall yield of 2-ethoxy benzoic acid obtained was 87.6%.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the invention, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be highly appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosures herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

I Claim:
1) A process for preparing alkoxy benzoic acid of formula (I), said process comprising the following steps of:
a) reacting a salt of hydroxy benzoic acid of formula (II) with an alkylating agent, in the presence of a polar aprotic solvent ,at a temperature in the range 25°C to 100°C and at a pressure in the range of 4- 10 kg/cm2, to form a product mixture containing alkoxy alkyl benzoate of formula (III);

b) removing the solvent from the product mixture to yield crude alkoxy alkyl benzoate of formula (III);
c) hydrolyzing the crude alkoxy alkyl benzoate of formula (III)at a pH in the range of 8-14 to yield a salt of an alkoxy benzoic acid of formula (IV) ; and
d) acidifying the alkoxy salt of benzoic acid to obtain ortho-alkoxy benzoic acid of formula (I).

The process as claimed in claim 1, wherein the polar aprotic solvent is selected from the group consisting of dimethyl acetamide (DMAc), N-methylpyrrolidinone (NMP), sulfolane, acetonitrile, dimethylsulfoxide and dimethyl formamide.
3) The process as claimed in claim 1, wherein the polar aprotic solvent is dimethylformamide.
4) The process as claimed in claim 1, wherein the amount of polar aprotic solvent used is in the range of 5 to 15 times v/w of the salicylate salt.
5) The process as claimed in claim 1, wherein the alkylating agent is an alkyl halide selected from the group consisting of methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl and butyl halide.
6) The process as claimed in claim 1, wherein the alkylating agent is methyl chloride gas.
7) The process as claimed in claim 1, wherein the hydroxy benzoic salt of formula (II) is disodium salt of salicylic acid.
8) The process as claimed in any one of the preceding claims, wherein the amount of methyl chloride is 1 to 4 moles per mole of disodium salt of salicylic acid.

9) The process as claimed in claim 1, wherein the alkoxy benzoic acid of formula (I) is ortho-methoxy benzoic acid.