DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
PROCESSES FOR PREPARATION AND PURIFICATION OF 5-CHLORO-2-NITROANILINE

2. APPLICANT(S):
APPLICANT NAME: M/S LASA SUPERGENERICS LIMITED
NATIONALITY : Indian company
ADDRESS : C-105, MIDC, Mahad, Dist. Raigad,
Maharashtra, India. Pin code - 402309

3. PREAMBLE TO THE DESCRIPTION:
PROVISIONAL
The following specification describes the invention. COMPLETE
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 preparing the 5-Chloro-2-nitroaniline.

BACKGROUND OF THE INVENTION:
5-Chloro-2-nitroaniline is a useful synthetic intermediate. It can be used as a reagent to synthesize benzamide derivatives as histone deacetylase inhibitors. It is an intermediate used to synthesize 1-Nitro Febantel (M264880), a Febantel (F227000) impurity. It is also a key raw material for synthesis of Fenbendazole.
There are few methods reported for preparing this compound. However the processes suffer from the drawbacks of by-products generation and non-separation of the product from reaction mixture. The cost of raw materials, solvents was also another concern.
The 2,4-diamino nitrobenzene impurity is seen to be a major concern with the methods primarily involving water.
There was a long standing need for an efficient and economic process for preparation of 5-Chloro-2-nitroaniline. Current invention tries to address this long standing need.

SUMMARY OF THE INVENTION:
Present invention provides a process for the preparation of 5-Chloro-2-nitroaniline. It also provide a process for purification of 5-Chloro-2-nitroaniline.
In first aspect, the present invention provides a process for preparing 5-Chloro-2-nitroaniline compound of the formula III that comprises

Compound of the Formula III
(i) reacting 1,3-Dichlorobenzene compound of formula I

Formula I
with nitric acid in presence of sulphuric acid to produce 2,4-Dichloro-1-nitrobenzene compound of formula II;

Formula II

(ii) reacting the 2,4-Dichloro-1-nitrobenzene compound of formula II with aqueous and gaseous ammonia mix to obtain 5-Chloro-2-nitroaniline compound of formula III.

Formula III

In second aspect, the invention provides a process for purification of 5-Chloro-2-nitroaniline compound of the formula III comprises
(i) heating crude 5-Chloro-2-nitroaniline compound of formula III

Formula III
in alcoholic solvent at reflux temperature in presence of sulphuric acid,
(ii) cooling and separating the solid mass followed by giving water wash to obtain the pure 5-Chloro-2-nitroaniline compound of formula III.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 depicts HPLC Chromatogram of 2,4-Dichloro-1-nitrobenzene obtained in example 1;
Figure 2 depicts HPLC Chromatogram of crude 5-Chloro-2-nitroaniline (compound of formula III) obtained in example 2;
Figure 3 depicts HPLC Chromatogram of purified 5-Chloro-2-nitroaniline (compound of formula III) obtained in example 3; and
Figure 4 depicts IR of purified 5-Chloro-2-nitroaniline (compound of formula III) obtained in example 3.
DETAILED DESCRIPTION OF THE INVENTION:
Present invention in first aspect relates to a novel process for the preparation of 5-Chloro-2-nitroaniline compound of the formula III. In said aspect of the invention, 1,3-Dichlorobenzene (compound of formula I) is reacted with nitric acid in presence of sulphuric acid to give 2,4-Dichloro-1-nitrobenzene (compound of formula II). The obtained solid 2,4-Dichloro-1-nitrobenzene is reacted with gaseous ammonia and water to obtain 5-Chloro-2-nitroaniline (compound of formula III).

In one suitable embodiment of first aspect, while preparing the 2,4-Dichloro-1-nitrobenzene (compound of formula II) the sulphuric acid is added with 1,3-Dichlorobenzene (compound of formula I) under stirring and chilling. The suitable temperature range is below room temperature. Then the nitric acid is added to this reaction mixture. After addition the reaction mixture is maintained till reaction completion. Preferably the quantities of sulphuric acid and nitric acid with respect to 1,3-Dichlorobenzene (compound of formula I) are taken in the weight ratios of 2:1 and 0.75:1 respectively.

Thereafter the reaction mass is added with water, heated and allowed for layer separation. Preferably it is heated in the temperature range of 46°C to 48°C for 01 to 02 hours. The product 2,4-Dichloro-1-nitrobenzene (compound of formula II) is obtained in the organic layer. It is preferably washed with water and sodium bicarbonate.

In another suitable embodiment of first aspect while preparing the 5-Chloro-2-nitroaniline (compound of formula III) from 2,4-Dichloro-1-nitrobenzene (compound of formula II), later is reacted with aqueous and gaseous ammonia mix to get 5-Chloro-2-nitroaniline. The reaction mixture of aqueous and gaseous ammonia and the 2,4-Dichloro-1-nitrobenzene is heated and maintained at elevated pressure to get the compound of formula III. Then the pressure is released, the product obtained is washed with water and dried.

Preferably the concentration of ammonia in aqueous ammonia is between the range of 18% To 20%. Preferably the aqueous ammonia and gaseous ammonia are taken in the range of 35% to 40% and 50%to 55% respectively with respect to 2,4-Dichloro-1-nitrobenzene (compound of formula II).

Preferably the reaction mixture of 2,4-Dichloro-1-nitrobenzene and aqueous and gaseous ammonia mix is heated up to 125°C and the pressure is maintained within the range of 18 to 24 kg/cm2. However, the temperature value of 125°C is non-limiting and the rise in temperature above it is also acceptable for the reaction as it doesn’t exert any adverse effect on the production.

The by-products generated in the processes of current invention are very less and the product is easily separable from the reaction mixture.

The second aspect relates to a novel process for the purification of 5-Chloro-2-nitroaniline compound of the formula III. In said aspect crude 5-Chloro-2-nitroaniline is heated in alcoholic solvent at reflux temperature in presence of sulphuric acid, then the obtained solid mass is cooled and separated followed by giving water wash to obtain the pure 5-Chloro-2-nitroaniline compound of formula III.

In one suitable embodiment, crude 5-Chloro-2-nitroaniline compound of formula III is added in the alcoholic solvent followed by addition of sulphuric acid. The sulphuric acid is preferably added in catalytic quantity. Then obtained reaction mixture is heated to the reflux temperature. Thereafter it is cooled and the solid mass is separated, washed with water and more preferably with hot water to get the pure 5-Chloro-2-nitroaniline compound of formula III. The alcoholic solvent may be one or more selected from a strait chain alcohol, branched alcohols and any combination thereof and preferably include methanol, ethanol, propanol and butanol. Preferably the alcoholic solvent with respect to crude 5-Chloro-2-nitroaniline is taken in the volume by weight ratio of 0.9 to 1.5. The sulphuric acid is preferably added in the range of 15% to 20% with respect to the crude 5-Chloro-2- nitroaniline.

The purity of more than 97% is achieved from the current process of purification.

Hereinafter, the invention is explained in detail in the following examples, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention in any way.

Example 1: Process for preparation of 2,4-Dichloro-1-nitrobenzene compound of formula II
2.99 moles of sulphuric acid was added with 1500kg 1,3-Dichlorobenzene (compound of formula I) under stirring and chilling. Then 0.75 times of 60% nitric acid (in Kg) was added to this reaction mixture below room temperature. The reaction mass was maintained for reaction completion. Thereafter the reaction mass is added with 1.33 volumes of water (in Lit.), heated at temperature between 46°C to 48°C and allowed layer separation. The organic layer was given water wash and 0.175 moles of sodium bicarbonate added to obtain 1910kg 2,4-Dichloro-1-nitrobenzene (compound of formula II)
Note: All quantities were used with respect to the quantity of compound of formula I use in the process.
HPLC chromatogram of 2,4-Dichloro-1-nitrobenzene as depicted in Figure 1

Example 2: Process for preparation of 5-Chloro-2-nitroaniline compound of formula III
2.133 volumes of 18% ammonia liquor (in Lit) was charged in pressure vessel followed by purging of 394kg gaseous ammonia at pressure 2kg/cm2. Then 750kg 2,4-Dichloro-1-nitrobenzene (compound of formula II) was added in pressure vessel. The reaction mixture was heated to 125°C and maintained at elevated pressure of 20-22 kg/cm2 for 17 hrs. Then the pressure was released over a period of 8-10 hours, the product obtained was given 2.67 volume of hot water (in Lit.) wash and air dried to get 740kg wet cake of 5-Chloro-2-nitroaniline (compound of formula III).
The process of current invention is economic.
Note: All quantities were used with respect to the quantity of compound of formula II use in the process.
HPLC chromatogram of crude 5-Chloro-2-nitroaniline as depicted in Figure 2
HPLC purity of crude 5-Chloro-2-nitroaniline: 92.28%;
Impurity 2,4-diaminonitrobenzene: 4.66%

Example 3: Process for the purification of 5-Chloro-2-nitroaniline compound of the formula III
0.854 Volume of fresh methanol and recycled methanol (in Lit.) was charged in glass line reactor. The moisture was maintained below 28% and then added 740kg crude 5-Chloro-2-nitroaniline followed by addition of 0.357 moles of sulphuric acid. The reaction mass was heated to 70-80°C and maintained for 5 hours, then cooled and the mother liquor was removed and the solid mass was centrifuged, given hot water wash till pH 6.0 - 7.0 to get 560kg wet cake of 5-Chloro-2-nitroaniline (compound of formula III) which on drying weighed 510kg.
Note: All quantities were used with respect to the quantity of crude 5-Chloro-2-nitroaniline use in the process.
HPLC chromatogram of pure 5-Chloro-2-nitroaniline as depicted in Figure 3
HPLC purity of crude 5-Chloro-2-nitroaniline: 92.28%;
Impurity 2,4-diaminonitrobenzene: 0.06%
IR of purified 5-Chloro-2-nitroaniline as depicted in Figure 4
,CLAIMS:Claim(s):
I/We claim:
1. A process for preparing 5-Chloro-2-nitroaniline compound of the formula III comprising

Compound of the Formula III
(i) reacting 1,3-Dichlorobenzene compound of formula I

Formula I
with nitric acid in presence of sulphuric acid to produce 2,4- Dichloro-1-nitrobenzene compound of formula II;

Formula II
and
(ii) reacting the 2,4-Dichloro-1-nitrobenzene compound of formula II with aqueous and gaseous ammonia mix to obtain 5-Chloro-2- nitroaniline compound of formula III.

Formula III

2. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 1, wherein in step (i) the sulphuric acid is added with 1,3-Dichlorobenzene (compound of formula I) under stirring and chilling.

3. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 1, wherein in step (i) the quantities of sulphuric acid and nitric acid with respect to 1,3-Dichlorobenzene (compound of formula I) are taken in the weight ratios of 2:1 and 0.75:1 respectively.

4. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 1, wherein in step (i) after the completion of reaction, the reaction mass is added with water, heated and allowed for layer separation.

5. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 4, wherein reaction mass is heated in the temperature range of 46°C to 48°C for 1 to 2 hours.

6. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claims 1 and 4, wherein the 2,4-Dichloro-1-nitrobenzene (compound of formula II) produced in step (i) is obtained in the organic layer and it is washed with water and sodium bicarbonate.

7. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 1, wherein in the aqueous and gaseous ammonia mix in step (ii), the concentration of ammonia in aqueous ammonia is between the range of 18% to 20% and the aqueous ammonia and gaseous ammonia are taken in the range of 35% to 40% and 50%to 55% respectively with respect to 2,4-Dichloro-1-nitrobenzene (compound of formula II).

8. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 1, wherein in step (ii) the reaction mixture of 2,4-Dichloro-1-nitrobenzene and aqueous and gaseous ammonia mix is heated up to 125°C and the pressure is maintained within the range of 18 to 24 kg/cm2.

9. The process for preparing 5-Chloro-2-nitroaniline compound of the formula III claimed in claim 1, wherein in step (ii) the product 5-Chloro-2-nitroaniline obtained is washed with water and dried.

10. A process for purification of 5-Chloro-2-nitroaniline compound of the formula III comprising
(i) heating crude 5-Chloro-2-nitroaniline compound of formula III

Formula III
in alcoholic solvent at reflux temperature in presence of sulphuric acid,
(ii) cooling and separating the solid mass followed by giving water wash to obtain the pure 5-Chloro-2-nitroaniline compound of formula III.

11. The process for purification of 5-Chloro-2-nitroaniline compound of the formula III as claimed in claim 10, wherein in step (i) the crude 5-Chloro-2-nitroaniline compound of formula III is added in the alcoholic solvent followed by addition of sulphuric acid.

12. The process for purification of 5-Chloro-2-nitroaniline compound of the formula III as claimed in claim 10, wherein in step (i) the alcoholic solvent is one or more selected from a strait chain alcohol, branched alcohols and any combination thereof.

13. The process for purification of 5-Chloro-2-nitroaniline compound of the formula III as claimed in claims 10 and 12, wherein in step (i) the alcoholic solvent is selected from methanol, ethanol, propanol and butanol.

14. The process for purification of 5-Chloro-2-nitroaniline compound of the formula III as claimed in claim 14, wherein in step (i) the alcoholic solvent with respect to crude 5-Chloro-2-nitroaniline is taken in the volume by weight ratio of 0.9 to 1.5.

15. The process for purification of 5-Chloro-2-nitroaniline compound of the formula III as claimed in claims 10 and 11, wherein in step (i) the sulphuric acid is added in the range of 15% to 20% with respect to the crude 5-Chloro-2- nitroaniline.

16. The process for purification of 5-Chloro-2-nitroaniline compound of the formula III as claimed in claim 10, wherein in step (ii) the cooled and separated solid mass is given hot water wash.

Dated this 19th day of June 2021
Signature: To be signed by electronic signature
Name: Adv. Parag M. more
OF INTELLECTUAL PLATFORM®
On Behalf of M/S LASA SUPERGENERICS LIMITED
Patent Agent for applicant
Patent Agent Regn. No. IN/PA-1688