Description:FIELD OF INVENTION
The present invention relates to a method of synthesis of indol 3-acetic acid with high purity. More particularly a method for synthesis of 1H-indol-3-ylacetic acid using indole and hydroxyacetic acid as reactants.

BACKGROUND OF THE INVENTION
1H-indol-3-ylacetic acid is a plant hormone which has utility as a rooting hormone and in other phytological applications which depend on its function as a growth hormone. Several methods for the synthesis of 1H-indol-3-ylacetic acid from indole and hydroxyacetic acid as a starting material have been reported.
Overall, the available 1H-indol-3-ylacetic acid synthesis options have many purity concerns which mainly stands as an unmet clinical need for the condition. Thus, there is need of pharmaceutical compositions which can compensate the limitation of available synthesis method and fulfill unmet needs in the obtaining 1H-indol-3-ylacetic acid with highest purity.
Thus, the inventors of the present invention have successfully addressed the drawbacks of the available synthesis method and came with a 1H-indol-3-ylacetic acid synthesis method which is 99.5% pure.
OBJECTIVE OF INVENTION
An object of the present invention is to provide a process for synthesis of 1H-indol-3-ylacetic acid using indole and hydroxyacetic acid as reactants.
Another object of the invention is to provide a process for synthesis of 1H-indol-3-ylacetic acid with high purity.
Yet another object of the invention is to provide an economical and efficient process for the synthesis of 1H-indol-3-ylacetic acid.

SUMMARY OF THE INVENTION
In one aspect the present invention relates to a method for synthesis of 1H-indol-3-ylacetic acid comprising the step of:
a) heating at least one mole of indole with at least one mole of hydroxyacetic acid and at least one mole of an alkali metal salt at temperature ranging from 150° C to 200° C for a period of time sufficient to obtain an alkali metal salt of indol-3-acetic acid.
b) extracting said alkali metal salt of indol-3-acetic acid using toluene at a pH ranging from 7 to 8 to obtain a first reaction mass.
c) extracting said first reaction mass using toluene at a temperature ranging from 50-55 °C at a pH ranging from 3 to 3.5 to obtain a second reaction mass.
d) filtering said second reaction mass to obtain a solid 1H-indol-3-ylacetic acid.
e) refluxing said solid 1H-indol-3-ylacetic acid in presence of acetic acid and activated carbon to obtain a suspended 1H-indol-3-ylacetic acid.
f) filtering said suspended 1H-indol-3-ylacetic acid followed by washing with acetic acid to obtain a 1H-indol-3-ylacetic acid.

DETAILED DESCRIPTION OF THE INVENTION
In the description that follows, a number of terms are used, the following definitions are provided to facilitate understanding of various aspects of the disclosure. In the specification, the word “comprising” is used as an open-ended term, substantially equivalent to the phrase “including, but not limited to,” and the word “comprises” has a corresponding meaning.
The terms and words used in the following description are not limited to the bibliographical meanings, but, are merely used to enable a clear and consistent understanding of the disclosure. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present disclosure are provided for illustration purpose only and not for the purpose of limiting the disclosure as defined by the appended claims and their equivalents.
In describing the embodiment of the invention, specific terminology is chosen for the sake of clarity. However, it is not intended that the invention be limited to the specific terms so selected and it is to be understood that such specific terms include all technical equivalents that operate in a similar manner to accomplish a similar purpose. As used herein, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements.
In one aspect, the present invention relates to method for synthesis of 1H-indol-3-ylacetic acid, wherein the process comprises the steps of:
a) heating at least one mole of indole with at least one mole of hydroxyacetic acid and at least one mole of an alkali metal salt at temperature ranging from 150° C to 200° C for a period of time sufficient to obtain an alkali metal salt of indol-3-acetic acid.
b) extracting said alkali metal salt of indol-3-acetic acid using toluene at a pH ranging from 7 to 8 to obtain a first reaction mass.
c) extracting said first reaction mass using toluene at a temperature ranging from 50-55 °C at a pH ranging from 3 to 3.5 to obtain a second reaction mass.
d) filtering said second reaction mass to obtain a solid 1H-indol-3-ylacetic acid.

e) refluxing said solid 1H-indol-3-ylacetic acid in presence of acetic acid and activated carbon to obtain a suspended 1H-indol-3-ylacetic acid.
f) filtering said suspended 1H-indol-3-ylacetic acid followed by washing with acetic acid to obtain a 1H-indol-3-ylacetic acid.

In one embodiment of the present invention provides a process for synthesis of compound of1H-indol-3-ylacetic acid from indole, hydrooxyacetic acid and alkali metal salt as starting material. In another embodiment, the mole fraction of indole is selected in the range of 0.3 to 0.35, more specifically 0.3. The mole fraction of hydrooxyacetic acid is selected in the range of 0.3 to 0.35, more specifically 0.33. The mole fraction of alkali metal salt is selected in the range of 0.4 to 0.43, more specifically 0.41.
In one embodiment, the hydrooxyacetic acid stock solution is 75% concentrated and the alkali metal salt solution is 80% concentrated.
In one embodiment of the present invention, wherein the alkali metal salt is selected from at least one but not limited to NaOH, KOH, Ca(OH)2, K2CO3, CaCO3.
In one embodiment of the present invention, the suspension of indole, hydrooxyacetic acid and alkali metal salt is heated using autoclave at the temperature ranging from 150° C to 200° C for a period of time sufficient to obtain an alkali metal salt of 1H-indol-3-ylacetic acid. In a preferred embodiment, the time period is selected from 48 to 60 hrs, more specifically 50 hrs. Once the mixture is heated to desired time and temperature in autoclave, the heated mixture is cooled till the reaction mass achieve room temperature to obtain alkali an metal salt of 1H-indol-3-ylacetic acid.
In another embodiment of the present application, the alkali metal salt of indol-3-acetic acid is extracted using toluene at a pH ranging from 7 to 8 to obtain a first reaction mass. In preferred embodiment, the potassium salt of1H-indol-3-ylacetic acid is extracted using toluene at a pH 7 to obtain a first reaction mass.
In another embodiment of the present application, the first reaction mass is extracted using toluene at a temperature ranging from 50-55 °C at a pH ranging from 3 to 3.5 to obtain a second reaction mass. In preferred embodiment, the first reaction mass is extracted using toluene 50? pH 3 to obtain a second reaction mass. In another embodiment, the extraction of potassium salt of 1H-indol-3-ylacetic acid is carried multiple times at varying pH. In preferred embodiment, the extraction of potassium salt of 1H-indol-3-ylacetic acid is done twice at different pH to obtain a second reaction mass.
In another embodiment of the present application, the second reaction mass is filtered to obtain a solid 1H-indol-3-ylacetic acid. In another embodiment filtration of second reaction mass is followed by washing with water to obtain a solid 1H-indol-3-ylacetic acid. The solid 1H-indol-3-ylacetic acid obtained from the above process has purity of 98. Therefore, the solid 1H-indol-3-ylacetic acid was further purified to increase the purity of the solid 1H-indol-3-ylacetic acid.
In one embodiment of the present application, the solid 1H-indol-3-ylacetic acid is refluxed in presence of acetic acid at 25° C wherein the content of acetic acidic is at least 1.5 times weight of the solid 1H-indol-3-ylacetic acid followed by the addition of activated charcoal to obtain clear solution. In another embodiment, filtering of suspended 1H-indol-3-ylacetic acid is carried out by passing through hyflo bed to obtain mother liquor comprising suspended 1H-indol-3-ylacetic acid.
Overall, the process as described in the above embodiments are efficient and economical.
The present invention is further elaborated with the help of the examples provided herein, but it should be noted by a person skilled in the art that these examples do not limit the scope of the present invention.
Experiments
Example 1
i. Preparation of 1H-indol-3-ylacetic acid

A suspension of 1H-indole (35.1 g, 0.30 mole), hydroxyacetic acid with 70% concentration (36.2 g, 0.31 mole) and potassium hydroxide with 85% concentration (27.3 g, 0.41 mole) was charge in autoclave and heat the reaction mixture to 150-200°C for 48hrs, after completion of reaction cool the reaction mass to 90°C and water 10 ml was added and allow to attend the reaction mass to room temperature. The reaction mixture was extracted using 30 ml toluene, adjust pH of aqueous layer to 7.0 using 30% HCl solution. The resulting reaction mass was extracted in 20 ml toluene at 50°C. The pH of aqueous layer was adjusted to 3.0 using con. HCl and filter the solid observed and wash 10 ml water gives title compound 80 g of 1H-indol-3-ylacetic acid, Purity 98.0%

ii. Purification of 1H-indol-3-ylacetic acid

80 g of 1H-indol-3-ylacetic acid was taken in acetic of 120 ml at 25° C. The reaction mixture was heated to 75-80reflux to obtain a clear solution, added 1.0 g activated charcoal and filter the reaction mass through hyflo bed. The resulting mother liquor was cool gradually to room temperature. The resulting suspension was filter and wash with 5 ml acetic acid gives title compound 78 g pure 1H-indol-3-ylacetic acid, purity 99.4%.

Example 2
i. Preparation of 1H-indol-3-ylacetic acid

A suspension of 1H-indole (35.1 g, 0.30 mole), hydroxyacetic acidwitth70% concentration (36.0 g, 0.33 mole) and potassium hydroxide with85% concentration (27.5 g, 0.41 mole) was charge in autoclave and heat the reaction mixture to 175°C for 55hrs, after completion of reaction cool the reaction mass to 100°C and water 10 ml was added and allow to attend the reaction mass to room temperature. The reaction mixture was extracted using 30 ml toluene, adjust pH of aqueous layer to 7.0 using 30% HCl solution. The resulting reaction mass was extracted in 20 ml toluene at 55°C. The pH of aqueous layer was adjusted to 3.5 using con. HCl and filter the solid observed and wash 10 ml water gives title compound 80 g of 1H-indol-3-ylacetic acid, Purity 98.0%

ii. Purification of 1H-indol-3-ylacetic acid

80 g of 1H-indol-3-ylacetic acid was taken in acetic of 120 ml at 25° C. The reaction mixture was heated to 75-80reflux to obtain a clear solution, added 1.0 g activated charcoal and filter the reaction mass through hyflo bed. The resulting mother liquor was cool gradually to room temperature. The resulting suspension was filter and wash with 5 ml acetic acid gives title compound 78 g pure 1H-indol-3-ylacetic acid, purity 99.5%.

Example 3
i. Preparation of 1H-indol-3-ylacetic acid

A suspension of 1H-indole (35.1 g, 0.30 mole), hydroxyacetic acid with 70% concertation (36.0 g, 0.33 mole) and potassium hydroxide with 85% concentration (27.5 g, 0.41 mole) was charge in autoclave and heat the reaction mixture to 175°C for 48-60hrs, after completion of reaction cool the reaction mass to 100°C and water 10 ml was added and allow to attend the reaction mass to room temperature. The reaction mixture was extracted using 30 ml toluene, adjust pH of aqueous layer to 8.0 using 30% HCl solution. The resulting reaction mass was extracted in 20 ml toluene at 55°C. The pH of aqueous layer was adjusted to 3.5 using con. HCl and filter the solid observed and wash 10 ml water gives title compound 80 g of 1H-indol-3-ylacetic acid, Purity 98.0%

ii. Purification of 1H-indol-3-ylacetic acid

80 g of 1H-indol-3-ylacetic acid was taken in acetic of 120 ml at 25° C. The reaction mixture was heated to 75-80reflux to obtain a clear solution, added 1.0 g activated charcoal and filter the reaction mass through hyflo bed. The resulting mother liquor was cool gradually to room temperature. The resulting suspension was filter and wash with 5 ml acetic acid gives title compound 78 g pure 1H-indol-3-ylacetic acid, purity 99.48%.

From the above three examples according to embodiments of the present application it is clear that maximum purity of 99.5 was achieved

Technical Advancements
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of:
• a method of syntheses of 1H-indol-3-ylacetic acid with high purity.
• a method of syntheses of 1H-indol-3-ylacetic acid which is efficient.
• a method of syntheses of 1H-indol-3-ylacetic acid which is economical.
, Claims:WE CLAIM:
1. A process for synthesis of synthesis of 1H-indol-3-ylacetic acid comprising the step of:
a) Heating at least one mole of indole with at least one mole of hydroxyacetic acid and at least one mole of an alkali metal salt at temperature ranging from 150° C. to 200° C for a period of time sufficient to obtain an alkali metal salt of indol-3-acetic acid.
b) extracting said alkali metal salt of indol-3-acetic acid using toluene at a pH ranging from 7 to 8 to obtain a first reaction mass.
c) extracting said first reaction mass using toluene at a temperature ranging from 50-55 °C at a pH ranging from 3 to 3.5 to obtain a second reaction mass.
d) filtering said second reaction mass to obtain a solid 1H-indol-3-ylacetic acid.
e) refluxing said solid 1H-indol-3-ylacetic acid in presence of acetic acid and activated carbon to obtain a suspended 1H-indol-3-ylacetic acid.
f) filtering said suspended 1H-indol-3-ylacetic acid followed by washing with acetic acid to obtain a 1H-indol-3-ylacetic acid.

2. The process as claimed in claim 1, wherein the mole fraction of indole is selected in the range of 0.3 to 0.35, the mole fraction of hydrooxyacetic acid is selected in the range of 0.3 to 0.35 and the mole fraction of alkali metal salt is selected in the range of 0.4 to 0.43.

3. The process as claimed in claim 1, wherein the alkali metal salt is selected from NaOH, KOH, Ca(OH)2, K2CO3, CaCO3.

4. The process as claimed in claim 1, wherein the time period is selected from 48 to 60hrs.
5. The process as claimed in claim 1, wherein the pH said alkali metal salt of indol-3-acetic acid is adjusted using HCl.

6. The process as claimed in claim 1, wherein the filtering of suspended 1H-indol-3-ylacetic acid is carried out by passing through hyflo bed.