Claims:We claim:

1. An improved process for preparation of 4-chloro-2-aminophenol comprises steps of:
a. charging 2,5-dichloronitrobenzene in a reactor;
b. adding water to above step;
c. adding caustic soda and heating up to 142ºC to148ºC with pressure about 3.5 to 4.0 kg/cm2 to obtain 4-chloro-2-nitrophenol in-situ;
d. coolingin-situ4-chloro-2-nitrophenol to 35º to 45ºC;
e. adding catalyst platinum or platinum on Charcoal/carbon;
f. passing hydrogen gas at the controlled temperature up to 95ºC and pressure up to 5.0 kg/cm2;
g. filtering the reaction mass at room temperature and separating the catalyst i.e. platinum or platinum charcoal / carbon for reuse;
h. adjusting acidic pH with hydrochloric acid;
i. optionally, adding activated carbon;
j. adjusting pH at about 3.5 to 6 using sodium hydroxide;
k. drying above wet mass at 60ºC to 80ºC to obtain 4-chloro-2-aminophenol.

2. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1(b), wherein water used in raw water or potable water.

3. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1(b), wherein 4-chloro-2-nitrophenol is used as in-situ (without isolating).

4. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1(e), wherein catalyst used is platinum or platinum on charcoal / carbon.

5. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1(f), wherein hydrogen is passed at controlled temperature up to 95ºC and pressure up to 5.0 kg/cm2 or up to unreacted starting material.

6. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1(g), wherein pH adjusted using hydrochloric acid is ranging from 2 to 3.

7. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1, wherein HPLC purity of 4-chloro-2-aminophenol is not less than 99%

8. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1, wherein titrimetric purity of 4-chloro-2-aminophenol is not less than 98%

9. An improved process for preparation of 4-chloro-2-aminophenol as claimed in claim-1, wherein catalyst is regenerated for using it in another time.

Dated this 20th day of June, 2020.

___________________________
PATEL MUKESHBHAI BABULAL
, Description:
FIELD OF THE INVENTION:
This invention relates to improved processes for preparing 4-chloro-2-aminophenol and derivatives thereof. More particularly to processes for preparing 4-chloro-2-aminophenol and its monohydrate derivative which involve novel combination of solvents, reagents and catalyst that yield, high HPLC and titrimetric purity.

BACKGROUND OF THE INVENTION:
4-chloro-2-aminophenol and its monohydrate derivative are general purpose compounds for use as industrial starting materials, and can be converted into synthetic intermediates of higher added value. The compounds have the
o-aminophenol structure which may serve as a reducing agent, and the degree of reducibility can be arbitrarily controlled by the introduction of a suitable substituent and the conversion of the nitro group into another functional group. In this sense, the derivatives are important as diversity of reducing agents or antioxidants or synthetic intermediates which are convertible into physiologically active compounds by the modification of the nitrogen atom.
4-chloro-2-aminophenol is an organic compound with molecular formula C6H6NOCl and molecular weight 143.57. In addition, 4-chloro-2-aminophenol (CAS: 95-85-2) may be represented as below:

4-chloro-2-aminophenol(I)

4-chloro-2-aminophenol is an intermediate used commonly for the manufacture of dyes and pharmaceuticals. 4-chloro-2-aminophenol is sometimes also called as either 5-Chloro-2-hydroxyaniline or 2-Amino-4-chlorophenol. It is white to brown crystals or powder or chunks. It has around 33.3 mg solubility in 1 ml of methanol and melting point ranging about 134 - 142°C.
CN101481311 discloses a method for preparing 4-chloro-2-nitrophenol, which comprises the steps of (a) a hydrolysis reaction of 2,5-dichloronitrobenzene and sodium hydroxide, (b) a 4-chloro-hydrolysis product Concentrated crystallization of 2-nitrophenol sodium, (c) refined 4-chloro-2-nitrophenol sodium, (d) neutralized 4-chloro-2-nitrophenol sodium to obtain 4-chloro-2-nitrophenol, and (e) spin-drying and packaging 4-chloro-2-nitrophenol, characterized in that in step (c), activated carbon is added to adsorb organic impurities in the reaction process, and then filtered to remove the activated carbon .
CN101481312 also discloses a method for preparing 4-chloro-2-nitrophenol, which comprises the steps of 2,5-dichloronitrobenzene hydrolysis, concentrated crystallization, refining, neutralization, spin-drying and packaging. Characterized in that the hydrolysis of 2,5-dichloro-nitrobenzene anti-temperature is controlled at 140 - 150°C, the reaction incubated for 8-12 hours. Activated carbon adsorption step was added trans be in the process of organic impurities, then filtered to remove the activated carbon .
CN101481313 similarly discloses a method for preparing 4-chloro-2-nitrophenol, which includes the steps of 2,5-dichloronitrobenzene hydrolysis, concentrated crystallization, purification, neutralization, spin-drying and packaging hydrolysis 5-dichloronitrobenzene, the reaction incubated for 8 hours. In the above method provided by the present invention, the amount of activated carbon added in step (c) can be determined according to the decolorization of the solution in the reaction process, and the amount of activated carbon added is generally 4-chloro-2-nitrophenol sodium solution.
CN101481310 discloses a method for preparing 4-chloro-2-nitrophenol, which includes the following steps like this way: (a) Hydrolysis: dissolve solid sodium hydroxide in a hydrolysis tank, and then add 2,5-dichloronitrobenzene, tight sealed reaction vessel was heated using a steam jacket to about 142-148 ° C, a reaction pressure of about 0.25-0.30mpa, anti-insulation should be 8-12 hours.(b) the concentration crystallization: After completion of the hydrolysis reaction, the reaction was concentrated under pressed into the crystallizer was stirred successively evaporated distilled off, cool, to give sodium 4-chloro-2-nitro-phenol red crystals.(c) Refining: add 4-chloro-2-nitrophenol sodium crystal to the refining tank with bottom water, add activated carbon , heat to about 60-90 °C to dissolve the crystal, then stir for 20-50 minutes, then Seal the refining tank, press air to press the 4-chloro-2-nitrophenol sodium solution into the filter press to remove the activated carbon , and collect the filtrate in the neutralization tank.(d) Cool the sodium 4-chloro-2-nitrophenol solution in the neutralization tank to 25-30 ° C and add industrial hydrochloric acid to adjust the pH = 5-5.5 light yellow 4-chloro-2-nitrophenol light yellow Crystals are precipitated;(e) Spin-drying and packaging: 4-chloro-2-nitrophenol crystals are spin-dried with a centrifugal dryer and packaged.
CN104860834 discloses a method for preparation of 2-amino-4-chlorophenol wherein following process is followed. 2,5-dichloro-nitrobenzene, caustic soda and water was added to a stainless steel autoclave reactor was heated at reflux for 10 - 12h, the reaction was filtered after the end of the control, set for the next batch the mother liquor Materials and solids are dried to obtain sodium p-chloro-o-nitrophenolate; put sodium p-chloro-o-nitrophenolate, solvent methanol and Raney nickel into the hydrogenation kettle, pass hydrogen to 1.5Mpa, continue until the end of the reaction, and filter to remove Raney Nickel and catalyst can be applied to the next batch of materials. After the mother liquor is distilled to remove methanol, water and hydrochloric acid are added to dissolve, activated carbon is decolorized. After filtration, the lye solid is precipitated, filtered and the filter cake is dried to obtain the intermediate 2-amino-4-chlorophenol.
CN106167471 also discloses a method for preparation of 2-amino-4-chlorophenol wherein following process is followed. The raw material 2,5-dichloronitrobenzene is heated and hydrolyzed in a strong alkaline aqueous solution to obtain a hydrolysate. The hydrolysis is heated to 120-150 ° C, and the reaction is16-24 hours; S12. After the reaction is completed, it is cooled, neutralized, and filtered. Dry to obtain 4-chloro-2-nitrophenol with a purity of =99%; S2, Catalytic synthesis: dissolve the 4-chloro-2-nitrophenol obtained in S1 in methanol, use Raney / Ni as the catalyst, and generate hydrogenation reduction 2-Amino-4-chlorophenol.
WO2011/077313 discloses a process for preparation of 2-chloro-2-aminophenolwherein 4-chloro-2-nitrophenol (1.0 equivalents), platinum (sulfide, 5% wt. on charcoal, reduced, dry, 4-5% weight) and methanol are stirred at 55 psi hydrogen overnight to yield 2-chloro-2-aminophenol.
CN104860834 discloses a process for preparation of 2-chloro-2-aminophenol wherein following process is followed. Adding 2,5-dichloronitrobenzene, liquid alkali and water to the stainless-steel reactor and heat to reflux for 10 ~ 12h. After the control reaction is completed, filter, the mother liquor is used for the next batch of materials, and the solid is dried to obtain chloro-o-nitro-nitrate. Sodium phenolate; put p-chloro-o-nitrophenol sodium, solvent methanol and Raney nickel in the hydrogenation kettle, pass hydrogen to 1.5Mpa, continue until the end of the reaction, filter to remove Raney nickel, the catalyst can be applied to the next batch of materials. The mother liquor is distilled to remove methanol, then added water and hydrochloric acid to dissolve, activated carbon is decolorized, after filtering to add lye solid precipitation, filtering, filter cake drying to obtain intermediate 2-amino-4-chlorophenol.
The inventors of the present invention noted from above all the prior-art that final products yield as well as purity is quite low and hence, they produce costly final product which is not so much helpful at the industrial scale. In addition, almost all the processes use hazardous solvents like ethanol and methanol. Further, after using these solvents, its termination into safer form is also very difficult and cost consuming process. Termination in safe form of above solvents is necessary to save our environment from more deterioration.
Hence, in view of all these prior-art publications, the inventors of the present invention came to a conclusion that there is still a need to prepare improved processes for preparation of 4-chloro-2-aminophenol, which can be prepared by simple and economically viable process, which is also eco-friendly. Moreover, the present invention is also economical in terms of catalyst. Here, after completion of the process, the inventors of the present invention regenerate the catalyst to reduce the hazardous waste in to the nature and thereby protecting the environment.
After many experiments, the inventors of the present invention have developed improved processes for preparation of 4-chloro-2-aminophenol and its monohydrate derivative wherein improved processes for preparation surprisingly very economical, less time consuming and avoid use of hazardous solvents and thereby stand as green process or eco-friendly process. This invention is further described in detail in later sections.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide improved processes for preparation of 4-chloro-2-aminophenol and monohydrate derivative thereof.
One more objective of the present invention is to provide improved processes for the preparation of 4-chloro-2-aminophenol which are economical as well as eco-friendly.
Another objective of the present invention is to provide improved processes for the preparation of 4-chloro-2-aminophenol wherein novel combination of solvents, reagents and catalysts are used to prepare the same in shorter time.
Another objective of the present invention is to provide improved processes for the preparation of 4-chloro-2-aminophenol wherein novel combination of solvents, reagents and catalysts are used to produce high yield with high HPLC purity and titrimetric purity.

SUMMARY OF THE INVENTION:
Despite of extensive research on process for preparation of 4-chloro-2-aminophenol, there were no reported research wherein use of hazardous solvents and reagents are avoided. Hence, those processes were harmful for the environment with very high extent. Also, those hazardous solvents and reagents also need purification to reduce the damage to the environment. Hence, the final product produced was costly. Against this, the inventors of the present invention have derived improved processes wherein the final product is produced without using hazardous solvents and reagents. Hence, processes of the present invention are economical and eco-friendly. In addition, processes of the present invention use novel combination of reagents, solvents and catalyst in such a way that final product has high HPLC purity and high titrimetric purity.
In one general aspect, improved process for the preparation of 4-chloro-2-aminophenol is done from 4-chloro-2-nitrophenol.
In yet another aspect, improved process for the preparation of 4-chloro-2-nitrophenol is done from 2,5-dichloronitrobenzene.
In yet another aspect, the present invention is also economical in terms of catalyst. Here, after completion of the process, the inventors of the present invention regenerate the catalyst to reduce the hazardous waste in to the nature and thereby protecting the environment.
Another embodiment according to the present invention, wherein the catalyst may be used in different purities.
In yet another embodiment of the present invention, wherein the final product is having HPLC purity not less than 99%, more preferably not less than 99.5%.
In another embodiment of the present invention, wherein the final product is having titrimetric purity not less than 98%.
In another embodiment of the present invention, wherein the reagents used include caustic soda and hydrogen gas.
Embodiments of the pharmaceutical composition may include use of platinum or platinum on charcoal / carbon as catalyst, which is later regenerated.
In another embodiment of the present invention, wherein the only solvent used is potable raw water instead of hazardous solvent and thereby making this process as eco-friendly.
In one embodiment, process for preparation of 4-chloro-2-nitrophenol as per the present invention comprising following steps:
a) charging 2,5-dichloronitrobenzene;
b) adding raw or potable water to above step-a;
c) adding caustic soda to the step-b mixture;
d) heating mixture obtained in step-c 142ºC to 148ºC and pressure 3.5 to 4.0 kg/cm2;
e) Maintain above reaction for 5-9hours to get the final product in-situ.
In another embodiment, process for preparation of 4-chloro-2-aminophenol as per the present invention comprising following steps:
a) cooling the in-situ4-chloro-2-nitrophenol obtained in above step;
b) adding catalyst –platinum or platinum on Charcoal/carbon;
c) Passing hydrogen gas at controlled temperature & pressure;
d) Adjusting pH with hydrochloric acid and add activated carbon and filter solution and again adjust pH with sodium hydroxide to obtain the final product.
The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1: shows a chromatogram in HPLC for the product as prepared by example-3

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.
In accordance with the present invention, process for preparing of 4-chloro-2-nitrophenol involves use of raw or potable water and caustic soda.
In accordance with the present invention, process for preparing of 4-chloro-2-aminophenol involves use of platinum or platinum on Charcoal/carbon and hydrogen gas.
The term "reagents" as used herein includes caustic soda and hydrogen gas.
The term "solvents" as used herein includes raw or potable water.
The term "catalysts" as used herein includes platinum or platinum on Charcoal/carbon.
The term "added" or "mixed" or “charge” or "adding" or "mixing" or “charging” as used herein are to be interpreted inclusively, unless the context requires otherwise.
In one embodiment, process for preparation of 4-chloro-2-nitrophenol as per the present invention comprising following steps:
a) charging 150 gm of 2,5-dichloronitrobenzene;
b) adding about 700 gm of raw or potable water to above step-a;
c) adding about 75 to 90 gm of caustic soda to the step-b mixture;
d) heating mixture obtained in step-c 142ºC to 148ºC at pressure ranging from 3.5 to 4 kg/cm2;
e) Maintain above reaction for 5-9 hours to get the final product in-situ.
In another embodiment, process for preparation of 4-chloro-2-aminophenol as per the present invention comprising following steps:
a) cooling at 35ºC to 45ºC the in-situ4-chloro-2-nitrophenol obtained in above step;
b) adding catalyst – platinum or platinum on Charcoal/carbon;
c) Passing hydrogen gas at controlled temperature up to 95ºC and pressure up to 5.0 kg/cm2;
d) Adjusting pH with hydrochloric acid and add activated carbon and filter solution and adjust pH with sodium hydroxide to obtain the final product.
In another embodiment, process for preparation of 4-chloro-2-aminophenol as per the present invention comprising following steps:
a) charging 150 gm of 2,5-dichloronitrobenzene;
b) adding about 700 gm of raw or potable water to above step-a;
c) adding about 75 to 90 gm of caustic soda to the step-b mixture;
d) heating mixture obtained in step-c 142ºC to 148ºCat pressure ranging from 3.5 to 4 kg/cm2;
e) maintain above reaction for 5-9 hours to get the final product in-situ;
f) cooling at 35ºC to 45ºC the in-situ4-chloro-2-nitrophenol obtained in above step;
g) adding catalyst – platinum or platinum on charcoal / carbon;
h) Passing hydrogen gas at controlled temperature up to 95ºC and pressure up to 5.0 kg/cm2;
i) Filtering the reaction mass at room temperature and separate catalyst i.e. platinum for reuse, once in-process TLC (thin-layer chromatography) complies;
j) adjusting pH with hydrochloric acid about 2 to 3;
k) adding activated carbon and stirring for 30 minutes;
l) Adjusting pH at about 3.5 to 6 using sodium hydroxide to obtain the final product.
The inventors of the present invention also noted that sequence of above processes is also crucial. Inventors had tried to change the sequence which led to poor results than the earlier one. Hence, not only the processes but also the sequence of these processes does play a significant role in preparation of the final product.
The inventors of the present invention have derived improved processes wherein the final product is produced without using hazardous solvents and reagents. Hence, processes of the present invention are economical and eco-friendly. In addition, processes of the present invention use novel combination of reagents, solvents and catalyst in such a way that final product has high HPLC purity and high titrimetric purity.
The final product of the present invention is having HPLC purity not less than 99%, more preferably not less than 99.5%. Further, the final product of the present invention is having titrimetric purity not less than 98%.
The present invention is also economical in terms of catalyst. Here, after completion of the process, the inventors of the present invention regenerate the catalyst to reduce the hazardous waste in to the nature and thereby protecting the environment. Here, the catalyst may be used in different purities.
The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Means, the foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention.
All such modifications and variations are intended to be included within the scope of the claims.

EXAMPLES

EXAMPLE-1: Preparation of 4-chloro-2-nitrophenol

Process for preparation:
150 gm of 2,5-dichloronitrobenzene was charged in a reactor. 700 gm of raw water or potable water was then added. After this, caustic soda flakes about
83 gm were added to above and heating was then started up to 142ºC to148ºC with the pressure about 3.5 to 4.0 kg/cm2. This condition was maintained for 5 to 9 hours. In-process thin layer chromatography was performed to check unreacted starting material. By this method, 4-chloro-2-nitrophenolwas obtained in-situ.

EXAMPLE-2: Preparation of 4-chloro-2-aminophenol (ROS Corrected)

Process for preparation:
4-chloro-2-nitrophenol as obtained in-situ in above example was then cooled to 35º to 45ºC using Cooling tower water. Then, catalyst platinum or Platinum on Charcoal/carbon was used. This catalyst was charged at 35º to 45ºC. Then, hydrogen gas was passed at controlled temperature up to 95ºC and pressure up to 5.0 kg/cm2. This condition was maintained up to unreacted starting material. In-process thin layer chromatography (TLC) was performed to check unreacted starting material. After TLC had complied, the reaction mass was then filtered and pH was adjusted from 2 to 3 using hydrochloric acid. Activated carbon was then optionally added and stirred for about 30 minutes and again filtered. Again, pH was adjusted using sodium hydroxide from 3.5 to 6.0 and final intermediate was isolated. This isolated slurry was then filtered and dried at temperature 60ºC to 80ºC to obtain the title compound.

EXAMPLE-3: Preparation of 4-chloro-2-aminophenol

Process for preparation:
150 gm of 2,5-dichloronitrobenzene was charged in a reactor. 700 gm of raw water or potable water was then added. After this, caustic soda flakes about 83 gm were added to above and heating was then started up to 142ºC to148ºC with the pressure about 3.5 to 4.0 kg/cm2. This condition was maintained for 5 to 9 hours. In process thin layer chromatography was performed to check unreacted starting material. By this method, 4-chloro-2-nitrophenol is obtained in-situ. This 4-chloro-2-nitrophenol was then cooled to 35º to 45ºC using Cooling tower water. Then, catalyst platinum or Platinum on Charcoal/carbon was used. This catalyst was charged at 35º to 45ºC. Then, hydrogen gas was passed at controlled temperature up to 95ºC and pressure up to 5.0 kg/cm2. This condition was maintained up to unreacted starting material. This condition was maintained up to consumption over or In-process thin layer chromatography (TLC) was performed to check unreacted starting material. After TLC had complied, the reaction mass was then filtered and pH was adjusted from 2 to 3 using hydrochloric acid. Add activated carbon was then optionally added and stirred for about 30 minutes and again filtered. Again, pH was adjusted using sodium hydroxide from 3.5 to 6.0 and final intermediate was isolated. This isolated slurry was then filtered and dried at temperature 60ºC to 80ºC to obtain the title compound. Yield of the final product obtained was ranging from 75.00 gm to 108.00 gm. The final product obtained had HPLC purity not less than 99% and titrimetric purity not less than 98%.
The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
The above-mentioned examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.