DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

PROCESS FOR PREPARATION OF 5-BROMO-1,2,3-TRICHLOROBENZENE

Hikal Limited, an Indian company, of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, India

The following specification 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 preparation of 5-bromo-1,2,3-trichlorobenzene of Formula (I) in simple, economical manner with high yield. The 5-bromo-1,2,3-trichlorobenzene of formula (I)is used in preparation of 1-(3,4,5-trichloro-phenyl)-2,2,2-trifluoro-ethanone which is a key intermediate of isoxazoline derivatives.

(I)

BACKGROUND OF THE INVENTION

The 5-bromo-1,2,3-trichlorobenzeneof formula (I) is building block for the preparation of halo-substituted-1-aryl-2,2,2-trifluoro-ethanonessuch as 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone,1-(3,4,5-trichloro-phenyl)-2,2,2-trifluoro-ethanone which are key intermediates in preparation of various veterinary active ingredients for example Sarolaner, Lotilaner.

(I)

The U.S. patent no.9,809,524B1 discloses the key intermediates of Sarolaner, Lotilaner and its synthesis using 5-bromo-1,2,3-trichlorobenzene as shown herein.

The U.S. patent no. 8,853,410B2 discloses the preparation of isoxazoline derivatives using halogenated styrene and halo-substituted-1-aryl-2,2,2-trifluoro-ethanones as shown in scheme-1. The halogenated styrene and halo-substituted-1-aryl-2,2,2-trifluoro-ethanones are prepared by using 5-halo-1,2,3-halo-substituted-benzeneas depicted in scheme-2 & 3.
Scheme 1–

Scheme 2 –

Scheme 3 –

The PCT patent application no. WO2014090918A1 discloses the preparation of Lotilaner using 5-bromo-1,2,3-trichlorobenzene as depicted below in scheme-4.
Scheme 4–

The U.S. patent no.8,466,115B2 discloses the preparation of Sarolaner using 5-bromo-1,3-dichloro-2-fluorobenzene as depicted below in scheme-5.
Scheme 5–

The 5-bromo-1,2,3-trichlorobenzene and its process of preparation is disclosed in various references. However, the process has one or more disadvantages and discussed herein below.

The bromination of aniline using N-bromosuccinimide (NBS) or potassium bromide (KBr),N,N-dimethyl-formamide (DMF), phosphorus oxychloride (POCl3) in solvent chloroform or dichloromethane (DCM) or solvent-free conditions (Synthetic Communications, 2009, 39(10), 1817-1824); using NBS in 1,4-dioxane (Tetrahedron Letters, 2010, 51(10), 1383-1385) or NBS in dichloroethane (Catalysis Letters, 2012, 142(3), 378-383)were disclosed in prior art. However, these processes are not industrially suitable.

The J. Chem. Soc. Trans. 1907,91, 1543-1554 discloses the chlorination of 4-bromoaniline under heating using concentrated hydrochloric acid (conc. HCl), where product 2,6-dichloro-4-bromoaniline was contaminated with trichloro aniline and oxidative byproducts with dark color (quinones and azo-compounds)resulted in lower yield.Also,purification of 2,6-dichloro-4-bromoanilinebecame difficult and required additional steps.

The Eur. J. Med. Chem., 2016, 124, 229-23 discloses the preparation of 4-amino-3,5-dichlorobenzenesulfonamide using sulfanilamide, 6N halogen acid, 30% hydrogen peroxide and recrystallization of the product from ethanol. This process involved large volume of solvent; thus, it is not industrially economical.

The J. Chem. Soc. Trans. 1917, 111, 41-50 discloses the preparation of tribromoaniline using 2,6-dibromosulphanilic acid, bromine, water. However, the document does not disclose the preparation of 4-amino-3,5-dichlorobenzenesulfonamide and 5-bromo-1,2,3-trichlorobenzene.

The U.S. patent no.9,975,823B2 discloses the preparation of 1,2,3-trichloro-5-bromo-benzene by reacting 1,2,3-trichlorobenzenewith a brominating agent in the presence of an acidic catalyst to obtain 1-bromo-2,3,4-trichloro benzene which then reacted with potassium tert-butoxidein tetrahydrofuran or 2-methyl-tetrahydrofuran.The 1,2,3-trichlorobenzeneis costlyreactant which consequently leads to high production cost.

The prior art discloses the preparation of 2,6-dichloro-4-bromoaniline in two steps i) by treating 2,6-dichlorosulphonamide with concentrated Sulfuric acid (conc. H2SO4) at high temperature (165°C to 190°C) to obtain 2,6-dichloro aniline; ii) followed by bromination to obtain 2,6-dichloro-4-bromoaniline. The disadvantages of the prior art processes are:a) more number ofreaction steps, b) high reaction temperature which is unsuitable and not economical.

The present invention provides process for preparation of 5-bromo-1,2,3-trichlorobenzeneof formula (I) with high yield,minimum by-products formation and in economically viable manner. First time, the present invention provides a process for preparation of compound of formula (IV) using compound of formula (III) in a single step at mild reaction conditions avoiding extreme reaction conditions.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process forpreparationof 5-bromo-1,2,3-trichlorobenzene of formula (I) using4-bromo-2,6-dichloroaniline of formula (IV) which is simple, economical and commercially viable.

In one embodiment, the present invention provides aprocess for preparationof 5-bromo-1,2,3-trichlorobenzene of formula (I), which comprises the steps:

(I)
a) Treating sulphanilamide of formula (II) with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain 4-amino-3,5-dichloro-benzenesulfonamide of formula (III);

(II) (III)
b) treating 4-amino-3,5-dichloro-benzenesulfonamide of formula (III) with brominating agent in suitable solvent to obtain 4-bromo-2,6-dichloroaniline of formula (IV);

(IV)
c) treating 4-bromo-2,6-dichloroaniline of formula (IV) with sodium nitrite, copper(I) chloride, hydrochloric acid to obtain 5-bromo-1,2,3-trichlorobenzene of formula (I).
In anotherembodiment, the present invention provides a process for preparationof 4-bromo-2,6-dichloroaniline of formula (IV), which comprises the steps:

(IV)
a) treating sulfanilamide of formula (II) with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain 4-amino-3,5-dichloro-benzenesulfonamide of formula (III);

(II) (III)
b) treating 4-amino-3,5-dichloro-benzenesulfonamide of formula (III) with brominating agent in suitable solvent to obtain a compound of formula (IV).

In another embodiment, the present invention provides a process for preparationof 4-bromo-2,6-dichloroanilineof formula (IV), which comprises the steps:

(IV)
a) treating aniline with suitable brominating agent in dimethylformamide to obtain 4-bromoaniline;
b) treating 4-bromoanilinewith hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain a compound of formula (IV).
In another embodiment, the present invention provides a process for preparation of 4-bromo-2,6-dichloroaniline of formula (IV) using4-amino-3,5-dichloro-benzenesulfonamide of formula (III) in one step at mild reaction condition.

In another embodiment, the present invention providesa process for preparationof 4-bromo-2,6-dichloroaniline of formula (IV), which comprises:

(IV) (III)
treating4-amino-3,5-dichloro-benzenesulfonamide of formula (III) with brominating agent in suitable solvent to obtain a compound of formula (IV).

In another embodiment, the present invention provides a process for preparationof 4-bromo-2,6-dichloroaniline of formula (IV), which comprises:

(IV)
treating 4-bromoaniline with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain a compound of formula (IV).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The term ‘solvent’, as used herein refers to one or mixture of solvents.

The instant invention relates to a process for preparationof 5-bromo-1,2,3-trichlorobenzene of formula (I) using4-bromo-2,6-dichloroaniline of formula (IV) which is simple, economical and commercially viable. Also, present invention further relates to a process for preparationof 4-bromo-2,6-dichloroaniline of formula (IV) using4-amino-3,5-dichloro-benzenesulfonamide of formula (III) in one step at mild reaction condition.Alternatively, the present invention provides a process for preparation of 4-bromo-2,6-dichloroanilineof formula (IV), which comprises the steps: a) treating aniline with suitable brominating agent in dimethylformamide to obtain 4-bromoaniline; b) treating 4-bromoaniline with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain a compound of formula (IV).

The process of the present invention is illustrated in the following general synthetic scheme 6:
Scheme 6 –

In anembodiment of the present invention, wherein the brominating agentis selected from a group consisting of bromine, N-bromosuccinamide (NBS) and the like.

In anotherembodiment of the present invention, wherein the suitable solvent is selected from a group consisting of water, alcoholic solvents such as methanol, ethanol, isopropanol; dimethylformamide, dichloromethane, dichloroethane, acetonitrile, chloroform, carbon tetrachloride and the like.

In anotherembodiment of the present invention, wherein minimum volumes of dimethylformamide is used to obtain 4-amino-3,5-dichloro-benzenesulfonamide of formula (III) from sulfanilamide of formula (II),therefore, reducing from 20 volumes to 6 to 12 volumes of solventwith respect to sulfanilamide of formula (II), which reduces generation of excess effluent, thereby making process eco-friendly.

In anotherembodiment of the present invention, wherein4-bromo-2,6-dichloroaniline of formula (IV) is prepared by using 4-amino-3,5-dichloro-benzenesulfonamide of formula (III), brominating agent and suitable solvent in one step at 25°C to 50°C.

In anotherembodiment of the present invention, wherein4-bromo-2,6-dichloroaniline of formula (IV) is prepared by using 4-amino-3,5-dichloro-benzenesulfonamide of formula (III), brominating agent and suitable solvent in one step at 25°C to 50°C; thus avoiding i) use of conc. H2SO4, ii) high reaction temperature i.e. 165°C to 190°C, iii) extraction with organic solvent during isolation process and, iv) distillation operations.

In anotherembodiment of the present invention, whereinbrominatinganiline of with brominating agent in dimethylformamide at roomtemperature to obtain 4-bromoanilinewith purity greater than 95%; In this embodiment4-bromoanilineis isolated without work up and without extraction using organic solvent in high yield and greater chemical purity.

In anotherembodiment of the present invention, wherein4-bromo-2,6-dichloroaniline of formula (IV) is prepared by using 4-bromoaniline of formula (VI) at room temperature without heating, avoiding organic solvent and distillation process. The4-bromo-2,6-dichloroaniline of formula (IV)is isolated by filtrationwithout work up and without extraction using organic solvents.

In anotherembodiment of the present invention, wherein4-bromo-2,6-dichloroanilineof formula (IV) is prepared by using 4-bromoaniline of formula (VI) at 5°C to 35°C and compound (IV) is isolated without extraction.

In anotherembodiment of the present invention, wherein5-bromo-1,2,3-trichlorobenzene of formula (I) is prepared by using 4-bromo-2,6-dichloroaniline of formula (IV) at 0°C to 20°C without heating.

The instant invention produces 5-bromo-1,2,3-trichlorobenzene of formula (I) and 4-bromo-2,6-dichloroanilineformula (IV) using low cost,readily available reactants and reagents.

In another embodiment of the present invention, wherein all the crude compound may be used as such or may be purified by distillation or crystallization or by different purification techniques well understood by person skilled in the art.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Experimental
Example 1: Preparation of 4-amino-3,5-dichloro-benzenesulfonamide (compound III)
To a solution of sulfanilamide(II) (100 g, 0.58 mol) in conc. HCl (500 ml, 5V), DMF (500 ml, 5V) was charged in 20 to 40 min at 25°C to 45°C. The reaction mixture was cooled at 15°C to 25°C. Hydrogen peroxide (200 ml (30 %), 2V) was slowlyadded over 20 to 30 min under stirring. The reaction mixture was stirred for 3 to 5hrs at 20°C to 25°C. After completion of reaction, the reaction mixturewas cooled at 0°C to 10°C, successively chilled water (1000 ml, 10V) was added and stirred for 2 to 4 hrs. The solid product was filtered, washed with chilled water and dried to get the compoundof formula (III) (120 g, 85.64 % yield).
1H NMR (400 MHz, DMSO-d6), d ppm: 7.62 (s, 2H), 7.25 (bs, 2H), 6.28(bs, 2H).
13C NMR (400 MHz, DMSO-d6), d ppm: 144.25, 131.36, 125.79, 117.05.
GC-MS: 240, Base m/z: 124.

Example 2a:Preparation of 4-bromo-2,6-dichloroaniline (compound IV)
To a cooled solution of compound of formula (III) (50 g, 0.207 mol) in MeOH (250 ml, 5V) and DMF (75 ml, 1.5V), bromine (26.5 ml, 0.518 mol) was slowly added at 0°C to 10°C for 15 to 35 min. The reaction mixture was warmed at 40°C to 50°C and stirred for 3 to 5hrs. After completion of reaction, reaction mixture was quenched using 20% aqueous solution of sodium metabisulfite (500 ml, 10V). Thereaction mass was stirred for 3 to 5hrs at room temperature to precipitate out the solid. The solid was filtered, washed with chilled water (100 ml, 2V), suck dried to obtain compound of formula (IV) (40 g, 80 % yield).
1H NMR (400 MHz, CDCl3), d ppm: 7.29 (s, 2H), 4.33 (bs, 2H).
13C NMR (400 MHz, CDCl3), d ppm: 139.35, 130.14, 119.91, 107.86.
GC-MS: 239, 241, Base m/z: 241.

Example 2b: Preparation of 4-bromo-2,6-dichloroaniline (compound IV)
The mixture of 4-bromoaniline (100 g, 0.58 mol) in conc.HCl (1000 ml, 10V) and DMF (600 ml, 6V), was stirred till clear solution for 20 to 40 min at 25°C to 35°C. The reaction mixture was cooled at 0°C to 5°C. Hydrogen peroxide (30%, 200 ml, 2V) was dropwise added over 10 to 20 min. The reaction mixture was warmed to 20°C to 25°C and stirred for 3 to 5 hrs. After completion ofreaction, the reaction mixture was cooled at 0°C to 5°C, successively chilled water (1000 ml, 10V) was added and stirred for 2 hrs. The solidwas filtered, washed with chilled water (400 ml, 4V) and dried to obtain the compound of formula (IV) (124.5 g, 88.90 % yield).
1H NMR (400 MHz, CDCl3), d ppm: 7.29 (s, 2H), 4.33 (bs, 2H).
13C NMR (100 MHz, CDCl3), d ppm: 139.35, 130.14, 119.91, 107.86.

Example 3: Preparation of 4-Bromoaniline (compound VI)
To a cooled solution of aniline (125 g, 1.34 mol) in a DMF (500 ml, 4V), N-bromosuccinamide (238.88g, 1.34 mol) was lot-wise charged at 0°C to 5°C for 30 to 60 min. The reaction mixture was stirred at 0°C to 10°Cfor 1 to 3hrs. After completion of reaction, the reaction mixturewas poured into chilled water (1250 ml, 10V) and stirred for 3hrs at 0°C to 5°C to precipitate out the solid. The solidwas filtered, washed with chilled water and dried to obtain compound of formula (VI)(184.6 g, 79.94 % yield, purity by GC>95%).
1H NMR (400 MHz, CDCl3), d ppm: 7.22 (dt, J1= 8.8 Hz, J2= 3.2 Hz, 2H), 6.53 (dt, J1= 8.8 Hz, J2= 3.2 Hz, 2H), 3.55 (bs, 2H).
13C NMR (400 MHz, CDCl3), d ppm: 145.33, 131.86, 116.61, 109.99.

Example 3: Preparation of 5-bromo-1,2,3-trichlorobenzene of formula (I)
To a solution of 4-bromo-2,6-dichloroaniline of formula (IV) (100 g, 0.415 mol) in conc.HCl (300 ml, 3V), dropwise aqueous solution of NaNO2 (34.4 g, 0.498 mol) in water (100 ml, 1V) was charged at -5°C to 10°Cand stirred for 1 hrs.. Simultaneously, the solution of Cu(I)Cl (20.5 g, 0.207 mol) in conc.HCl (200 ml, 2V) was prepared and stirredat 5°C to 15°C. To this solution, diazonium salt solution was added slowly at 5°C to 20°C and stirred for 1 hrs. After completion of reaction, water (700 ml, 7V) was added to the reaction mixture. The reaction mass extracted with toluene, toluene layer washed with water and the crude product was purified by distillation to obtain compound of formula (I) as a white solid (75.6 g, 70% yield, purity by GC>97%).
1H NMR (400 MHz, CDCl3), d ppm: 7.49 (s, 2H).
13C NMR (400 MHz, CDCl3), d ppm: 134.90, 131.30, 130.85, 119.76.
GC-MS: 258, Base m/z: 260.
,CLAIMS:We claim:

1. A process for preparation of 5-bromo-1,2,3-trichlorobenzene of formula (I), which comprises the steps:

(I)
a) treating sulphanilamide of formula (II) with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain 4-amino-3,5-dichloro-benzenesulfonamide of formula (III);

(II) (III)
b) treating 4-amino-3,5-dichloro-benzenesulfonamide of formula (III) with a brominating agent in a solvent to obtain 4-bromo-2,6-dichloroaniline of formula (IV);

(IV)
c) treating 4-bromo-2,6-dichloroaniline of formula (IV) with sodium nitrite, copper(I) chloride, hydrochloric acid to obtain 5-bromo-1,2,3-trichlorobenzene of formula (I).

2. The process as claimed in claim 1 wherein, the process for preparation of 4-bromo-2,6-dichloroaniline of formula (IV)comprises the steps:

(IV)
a) treating aniline with a brominating agent in dimethylformamide to obtain 4-bromoaniline;
b) treating 4-bromoaniline with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain a compound of formula (IV).

3. The process as claimed in claim 1 wherein, the process for preparation of 4-bromo-2,6-dichloroaniline of formula (IV) comprises:
treating 4-amino-3,5-dichloro-benzenesulfonamide of formula (III) with a brominating agent in a solvent to obtain a compound of formula (IV),
(OR)
treating 4-bromoaniline with hydrogen peroxide, hydrochloric acid in dimethylformamide to obtain a compound of formula (IV).

4. The process as claimed in claim 1 to 3wherein,the brominating agent is selected from a group consisting of bromine and N-bromosuccinamide (NBS); and the solvent is selected from a group consisting of water, alcoholic solvents such as methanol, ethanol, isopropanol; dimethylformamide, dichloromethane, dichloroethane, acetonitrile, chloroform and carbon tetrachloride.

5. The process as claimed in claim 1wherein, the dimethylformamide is used in 6 to 12 volumes.

6. The process as claimed in claim 1 to 3 wherein,4-bromo-2,6-dichloroaniline of formula (IV) is prepared by using 4-amino-3,5-dichloro-benzenesulfonamide of formula (III), brominating agent and solvent in one step at 25°C to 50°C.

7. The process as claimed in claim 1 to 3wherein, bromination of aniline with brominating agent in dimethylformamide is performed at room temperature to obtain 4-bromoaniline of formula (VI) with purity greater than 95%; where 4-bromoaniline is isolated without work up and without extraction.

8. The process as claimed in claim 1 to 3wherein,4-bromo-2,6-dichloroanilineof formula (IV) is prepared by using 4-bromoaniline of formula (VI) at room temperature without heating, avoiding organic solvent and distillation process; where4-bromo-2,6-dichloroaniline of formula (IV)is isolated by filtration without work up and without extraction.

9. The process as claimed in claim 1 to 3wherein,4-bromo-2,6-dichloroanilineof formula (IV) is prepared by using 4-bromoaniline of formula (VI) at 5°C to 35°C and isolated without extraction.

10. The process as claimed in claim 1 wherein,5-bromo-1,2,3-trichlorobenzene of formula (I) is prepared by using 4-bromo-2,6-dichloroaniline of formula (IV) at 0°C to 20°C without heating.