EFFICIENT, ECONOMIC AND ECO-FRIENDLY PROCESS FOR THE PREPARATION OF 4-BROMO-ORTHO-PHENYLENE-DIAMINE

FIELD OF INVENTION:
The present invention relates to an efficient, economic and eco-friendly process for preparing 4-
bromo-ortho-phenylene-diamine (compound of structural formula I) as shown below. Further,
the process gives good yield and good purity.

Formula I
BACKGROUND OF INVENTION:
In Chemical and Pharmaceutical industries 4-bromo-ortho-phenylene-diamine (compound of structural formula I) is very useful intermediate. It's most recent application is found in the preparation of active pharmaceutical ingredient Ledipasvir which is approved by US FDA for treatment of hepatitis C. Conventionally compound of structural formula I is synthesized by various methods disclosed as below.
As shown in US Patent 5,770,617, 2-nitroanilin in dichloromethane is reacted with 2,4,4,6-tetrabromo-2,5-cyclohexadienone at -10°C to -0°C for 1 hour to obtain 4-Bromo-2-nitroaniline which is then hydrogenated with tin (II) chloride in ethanol to get compound of structural formula I, as depicted below in scheme I:


CN103 724276 described a process of preparing compound of structural formula I in which 2-nitroanilin in acetic acid is reacted with N-Bromosuccinimide to get 4-bromo-2-nitroaniline, then the nitro group is reduced in ethanol with sodium dithionite, stirred and heated the reaction mixture under reflux for 48 hrs to get compound of structural formula I, as depicted below in scheme II:

Scheme II
However, in such process the 4-bromo-2-nitroaniline is precipitated by adding water to acetic acid solution and then the mixture of acetic acid-water is discarded. This increases the COD and the BOD in effluent. The second step needs 48 hrs. reflux.
Tetrahedron Letters, 44(21), 4085-88; 2003 described process for preparing compound of structural formula I as reacting 2-nitroaniline with hydrobromide in presence of hydrogen peroxide at 0°C for 12 hours.
Organic Preparations and Procedures International, 32(5), 485-488; 2000 mentioned reduction of 4-bromo-2-nitroaniline in ethanol with hydrogen gas using Nickel catalyst.

However aforementioned methods in prior art had various disadvantages like low yield, long reaction hours, necessity of cooling tools to maintain lower temperature for longer hours, expensive reduction steps due to high cost of tin and nickel, need of excessive processing for heavy metal removal from product, necessity of specialized infrastructure to store, handle and employ in reaction the flammable and explosive gas like hydrogen, need of specialized infrastructure for maintenance of hydrogen pressure etc. Overall, the processes were inconvenient, un- economic and non-eco friendly.
Present invention provides an efficient, economic and eco-friendly process for preparing compound of structural formula I, in good yield and with good purity.
SUMMARY OF INVENTION:
Present invention provides a process for preparing 4-bromo-ortho-phenylene-diamine (compound of structural formula I) comprising;

Formula I
a) reacting 2-nitroaniline in aromatic hydrocarbon solvent with brominating agent at temperature range of 45°C to 50°C to obtain 4-bromo-2-nitroaniline

b) reducing the obtained 4-bromo-2-nitroaniline in water with Sodium hydrogen sulfide within the temperature range of 60°C to 90°C to obtain compound of structural formula I.


In this process 4-bromo-2-nitroaniline is obtained in step a). The solvent is recovered by simply filtration or distillation method and the residue obtained is used in step b) reduction reaction. The compound of structural formula I obtained in step b) can be precipitated from aqueous solution by adjusting pH between 10 to 11. The purity of compound of structural formula I obtained in step b) can be further enhanced by adding a simple solvents extraction step before precipitation. In this solvents extraction step, the compound of structural formula I which obtained in step b) in its aqueous solution state is first extracted in water immiscible solvent at neutral pH and then again extracted in fresh water at acidic pH and then precipitated at pH 10-11.
BRIEF DESCRIPTION OF THE DRAWINGS:
For more complete understanding of the features and advantages of the present invention,
reference is now made to the detailed description of the invention and the accompanying figure
and in which:
Figure 1: depicts IR of 4-bromo-2-nitroaniline standard
Figure 2: depicts IR of 4-bromo-2-nitroaniline obtained in example 1
Figures 3 to 10: depict GC chromatogram indicating purity of 4-bromo-2-nitroaniline obtained in
examples 1 to 8
Figure 11: depicts IR of 4-bromo-ortho-phenylene-diamine standard
Figure 12: depicts IR of 4-bromo-ortho-phenylene-diamine obtained in example 9
Figure 13 to 17: depict GC Chromatogram indicating purity of 4-bromo-ortho-phenylene-
diamine obtained in examples 9 to 13
DESCRIPTION OF INVENTION:
The process of present invention comprises two main conversion steps. The first being bromination and second is reduction.

In bromination, 2-nitroaniline is brominated in aromatic hydrocarbon solvent at 45°C to 50°C to obtain product 4-bromo-2-nitroaniline. The solvent is recovered by filtration or distillation method and the residue obtained is used in step b) for reduction. The recovered solvent can be reused. In fact, it can be reused in next reaction cycle. Aromatic hydrocarbons have a benzene ring structure. Such solvents are preferably selected from but not limited to the group consisting of toluene, chlorobenzene, xylene and heptane. Suitable bromination agent includes but not limited to N-Bromosuccinamide, 1,3 dibromo-5,5- dimethyl hydantion. Although the reaction time is dependent on the quantities of reagents and the design of reactor, 1 to 2 hrs is sufficient time for maximum conversion.
In reduction, 4-bromo-2-nitroaniline is reduced in water using Sodium hydrogen sulfide to get compound of structural formula I. This eliminates the possibility of heavy metal contamination in final product. Also this process is operationally safe. Preferably this reduction reaction is carried out within the temperature range of 75°C to 85°C. The compound of structural formula I obtained through reduction is isolated from the aqueous solution. One of the easy ways of isolation is precipitation from aqueous solution by adjusting pH to 10 - 11 and separating the precipitate. Precipitated product can be separated by various methods including solvent evaporation, filtration etc. Preferably filtration is the simplest and economic method for separation. The purity of compound of structural formula I can be further enhanced by adding a simple solvents extraction step before precipitation. In this solvents extraction step, the compound of structural formula I obtained in its aqueous solution state is first extracted in water immiscible solvent at neutral pH and then again extracted in fresh water at acidic pH. Then it is precipitated at the pH value between 10-11. Simultaneously, after extracting the compound of formula I in water at acidic pH, the water immiscible solvent is recovered and preserved for reuse. Examples of suitable water immiscible solvent are methylenedichloride, toluene, monochlorobenzene etc.
Faster conversion rate at easily manageable temperature, solvent recycling, solvent recovery and no use of hazardous reagents make the process efficient, economic and eco-friendly. Further, the process gives good yield and good purity at both steps.

The present invention is farther described with the help of the following examples, which are given by way of illustration and should not be construed to limit the scope of the invention in any manner.
EXAMPLES:
Stage 1: Preparation of 4-bromo-2-nitroaniline
Examples 1 to 3: Preparation of 4-bromo-2-nitroaniline in fresh toluene
Example 1:
In a clean and dry reaction assembly was charged toluene (400 ml), nitro aniline (lOOgms) and
N-bromo succinimide (142gms). The temperature was maintained at 45-50°C for 50 minutes to
obtain 4-bromo-2-nitroaniline. The mixture was cooled to 15-20°C for an hour and filtered to
isolate the product. Isolated product washed with toluene, then slurred in water, stirred and
filtered. It again given water wash.
Molar Yield: 79.62%
Purity: 95.30%
IR: As depicted in Figure 2
GC Chromatogram: As depicted in Figure 3.
The filtered toluene was recovered in a clean and dry container for re-use.
Example 2:
When procedure of example 1 is performed with below mentioned parameters, 4-bromo-2-nitroaniline was obtained in 82.80% molar yield and 98.59% purity:

Solvent/Reagent Toluene O-Nitroaniline N-Bromosuccinamide
Quantity 2000ml 500gm 709gm

Step
Time

Maintaining temperature at 45-50°C
1 hr 20 minutes

GC Chromatogram: As depicted in Figure 4.
Example 3:

In a clean and dry reaction assembly was charged toluene (40 ml), nitro aniline (10gms) and 1,3
dibromo - 5,5-dimethyl hydantoin (11.38gms). The temperature .was maintained at 45-50°C for
40 minutes to obtain 4-bromo-2-nitroaniline. The mixture was cooled.to 15-20°C for an hour and
filtered to isolate the product. Isolated product washed with toluene.
Molar Yield: 58.62%
Purity: 92.98%
GC Chromatogram: As depicted in Figure 5.
The filtered toluene was recovered in a clean and dry container for re-use.
Example 4: Preparation of 4-bromo-2-nitroaniline in recovered toluene
In a clean and dry reaction assembly was charged recovered toluene (400 ml), nitro aniline
(lOOgms) and N-bromo succinimide (141.8gms). The temperature was maintained at 45-50°C for
50 minutes to obtain 4-bromo-2-nitroaniline. 3 liter water slurry wash was given at 45°C for 1 hr
and filtered to obtain product. Isolated product washed with water.
Molar Yield: 80.25%
Purity: 98.48%
GC Chromatogram: As depicted in Figure 6.
Examples 5 to 7: Preparation of 4-bromo-2-nitroaniline in fresh Monochlorobenzene Example 5:
In a clean and dry reaction assembly was charged monochlorobenzene (400 ml), nitro aniline
(lOOgms) and N-bromo succinimide (142gms). The temperature was maintained at 45-50°C for
lhour 25 minutes to obtain 4-bromo-2-nitroaniline. The mixture was cooled to 15-20°C for an
hour and filtered to isolate the product. Isolated product washed with monochlorobenzene, then
slurred in water, heated, stirred and filtered. It again given water wash.
Molar Yield: 82.80%
Purity: 98.42%
GC Chromatogram: As depicted in Figure 7.
The filtered monochlorobenzene was recovered in a clean and dry container for re-use.

Example 6:
When procedure of example 5 is performed with below mentioned parameters, 4-bromo-2-nitroaniline was obtained in 80.23% molar yield and 98.06% purity:

Solvent/Reagent Monochlorobenzene O-Nitroaniline N-Bromosuccinamide
Quantity 2000ml 500gm 710gm

Step Maintaining temperature at 45-50°C
Time lhr
GC Chromatogram: As depicted in Figure 8.
Example 7:
In a clean and dry reaction assembly was charged monochlorobenzene (40 ml), nitro aniline
(lOgms) and 1,3 dibromo - 5,5-dimethyl hydantoin (11.38gms). The temperature was maintained
at 45-50°C for 35 minutes to obtain 4-bromo-2-nitroaniline. The mixture was cooled to 15-20°C
for an hour and filtered to isolate the product. Isolated product washed with toluene.
Molar Yield: 61.53%
Purity: 92.59%
GC Chromatogram: As depicted in Figure 9.
The filtered monochlorobenzene was recovered in a clean and dry container for re-use.
Example 8: Preparation of 4-bromo-2-nitroaniline in recovered Monochlorobenzene
When procedure of example 5 is performed with below mentioned parameters, 4-bromo-2-nitroaniline was obtained in 80.13% molar yield and 97.28%) purity:

Solvent/Reagent Recovered Monochlorobenzene O-Nitroaniline N-Bromosuccinamide
Quantity 800ml 200gm 284gms

Step Maintaining temperature at 45-50°C
Time lhr 30 minutes
GC Chromatogram: As depicted in Figure 10.
Stage 2: Preparation of 4-bromo-ortho-phenylene-diamine

Example 9: Preparation of 4-bromo-ortho-phenylene-diamine and its precipitation
In a clean and dry reaction assembly was charged water (200ml) and 4-bromo-2-nitroaniline (100gms). Temperature was raised and maintained between 60-68°C and started addition of Sodium hydrogen sulfide (220gms) in its 30% aqueous solution form. After complete addition, the temperature was raised and maintained between 80 to 85C° till 4-bromo-2-nitroaniline is below 0.5%. The reaction mixture was cooled to room temperature and pH was adjusted between 10 to 11 with hydrochloric acid. Precipitated product was filtered and dried.
Molar Yield: 70.57%
Purity: 83.84%
IR: As depicted in Figure 12.
GC Chromatogram: As depicted in Figure 13.
Examples 10 to 13: Preparation of 4-bromo-ortho-phenylene-diamine and performing liquid - liquid extraction before its precipitation Example 10:
In a clean and dry reaction assembly was charged water (440ml) and 4-bromo-2-nitroaniline (200gms). Temperature was raised and maintained between 60-70°C and started addition of Sodium hydrogen sulfide (440gms) in its 30% aqueous solution form. After complete addition,. the temperature was raised and maintained between 75 to 85C° till 4-bromo-2-nitroaniline is below 0.5%. The reaction mixture was cooled to 30-35°C and extracted with 200ml of methylenedichloride. Extraction repeated for next two cycles using 200ml mefhylenedichloride each time. All organic layers were mixed together, washed with water till neutral pH and kept aside. This isolated organic layer was extracted twice with aqueous HC1 (first extraction with 80ml HC1 in 1000ml water and second with 20mlHCl in 500ml water). The organic layer i.e. methylenedichloride layer was preserved for re-use. Final aqueous extract was given charcoal treatment, cooled to 10°C and product 4-bromo-ortho-phenylene-diamine was precipitated by pH adjustment at 10 to 11 using 20% aqueous NaOH. Precipitated product was filtered and given water wash. As per need, aqueous hydrose solution was used to avoid color change while pH adjustment.

Molar Yield: 63.82%
Purity: 100%
GC Chromatogram: As depicted in Figure 14.
Example 11:
In a clean and dry reaction assembly was charged water (800ml) and 4-bromo-2-nitroaniline (400gms). Temperature was raised and maintained between 60-68°C and started addition of Sodium hydrogen sulfide (880gms) in its 30% aqueous solution form. After complete addition, the temperature was raised and maintained between 75 to 85C° till 4-bromo-2-nitroaniline is below 0.5%. The reaction mixture was cooled to 30-35°C and extracted with 400ml of methylenedichloride. Extraction repeated for next two cycles using 200ml methylenedichloride each time. All organic layers were mixed together, washed with water till neutral pH and kept aside. This isolated organic layer was extracted twice with aqueous HC1 (first extraction with 160ml HC1 in 2000ml water and second with 40ml HC1 in 500ml water). The organic layer i.e. methylenedichloride layer was preserved for re-use. Final aqueous extract was given charcoal treatment, cooled to 15 to 20°C and product 4-bromo-ortho-phenylene-diamine was precipitated by pH adjustment at 10 to 11 using 20% aqueous NaOH. Precipitated product was filtered and given water wash. As per need, aqueous hydrose solution was used to avoid color change while pH adjustment.
Molar Yield: 67.44%
Purity: 99.87%
GC Chromatogram: As depicted in Figure 15
Example 12:
In a clean and dry reaction assembly was charged water (200ml) and 4-bromo-2-nitroaniline (lOOgms). Temperature was raised to 50°C and started addition of Sodium hydrogen sulfide (220gms) in its 30% aqueous solution form. After complete addition, the temperature was raised and maintained between 75 to 85°C till 4-bromo-2-nitroaniline is below 0.5%. The reaction mixture was cooled to 30°C and extracted with 100ml of toluene. Extraction repeated for next two cycles using 100ml toluene each time. All organic layers were mixed together, washed with

water till neutral pH and kept aside. This isolated organic layer was extracted twice with aqueous HC1 (first extraction with 40ml HC1 in 500ml water and second with lOmlHCl in 250ml water). The organic layer i.e. toluene layer was preserved for re-use. Final aqueous extract was given charcoal treatment, cooled to 15 to 20°C and product 4-bromo-ortho-phenylene-diamine was precipitated by pH adjustment at 10 to 11 using 20% aqueous NaOH. Precipitated product was filtered and given water wash. As per need, aqueous hydrose solution was used to avoid color change while pH adjustment.
Molar Yield: 66.28%
Purity: 99.90%
GC Chromatogram: As depicted in Figure 16
Example 13:
In a clean and dry reaction assembly was charged water (200ml) and 4-bromo-2-nitroaniline (lOOgms). Temperature was raised to 50°C and started addition of Sodium hydrogen sulfide (220gms) in its 30% aqueous solution form. After complete addition, the temperature was raised and maintained between 75 to 85C° till 4-bromo-2-nitroaniline is below 0.5%. The reaction mixture was cooled to 30°C and extracted with 100ml of monochlorobenzene. Extraction repeated for next two cycles using 100ml monochlorobenzene each time. All organic layers were mixed together, washed with water till neutral pH and kept aside. This isolated organic layer was extracted twice with aqueous HC1 (first extraction with 40ml HC1 in 500ml water and second with lOmlHCl in 250ml water). The organic layer i.e. monochlorobenzene layer was preserved for re-use. Final aqueous extract was given charcoal treatment, cooled to 15 to 20°C and product 4-bromo-ortho-phenylene-diamine was precipitated by pH adjustment at 10 toll using 20% aqueous NaOH. Precipitated product was filtered and given water wash. As per need, aqueous hydrose solution was used to avoid color change while pH adjustment.
Molar Yield: 64.98%
Purity: 99.85%
GC Chromatogram: As depicted in Figure 17

We claim:
1. A process for preparing 4-bromo-ortho-phenylene-diamine (compound of structural formula I) comprising

a) reacting 2-nitroaniline in aromatic hydrocarbon solvent with brominating agent at temperature range of 45°C to 50°C to obtain 4-bromo-2-nitroaniline,

b) reducing the obtained 4-bromo-2-nitroaniline in water with Sodium hydrogen sulfide within the temperature range of 75°C to 85°C to obtain compound of structural formula I.

2. The process as claimed in claim 1, wherein the brominating agent is selected from N-bromo succinimide and 1,3 dibromo - 5,5-dimethyl hydantoin.
3. The process as claimed in claim 1, wherein aromatic hydrocarbon solvent in step a) are selected from the group consisting of toluene, chlorobenzene, xylene and heptane.

4. The process as claimed in claim 1, wherein after obtaining 4-bromo-2-nitroaniline in step a) the aromatic hydrocarbon solvent is recovered by filtration or by distillation for reuse.
5. The process as claimed in claim 1, wherein 4-bromo-ortho-phenylene-diamine obtained in step b) is isolated by precipitating it out at pH value between 10 to 11.
6. The process as claimed in claim 5, further comprise solvents extraction step before isolation of 4-bromo-ortho-phenylene-diamine by precipitation.
7. The process as claimed in claim 5 and claim 6, wherein in solvents extraction 4-bromo-ortho-phenylene-diamine obtained in step b) in its aqueous solution state is first extracted in water immiscible solvent at neutral pH and then extracted in fresh water at acidic pH.
8. The process as claimed in claim 7, wherein the water immiscible solvent is selected from methylenedichloride, toluene and monochlorobenzene.
9. The process as claimed in claim 8 and 9, wherein after extraction of 4-bromo-ortho-phenylene-diamine from water immiscible solvent in fresh water at acidic pH, the water immiscible solvent is recovered for reuse.
10. A process for purification of 4-bromo-ortho-phenylene-diamine comprising extracting 4-bromo-ortho-phenylene-diamine in water immiscible solvent at neutral pH, then extracting in fresh water at acidic pH and precipitating at pH value between 10 to 11.