FILED OF THE INVENTION
The present invention relates to preparation of dihalobromobenzene;

Formula-1

BACKGROND OF THE INVENTION
The dihalobromobenzene compounds are important pharmaceutical and agriculture, intermediates for synthesis of certain herbicidal.
Japanese Patent No. 075487 discloses diazotization and bromination of 2-chloro-4-fluoroaniline to form 1-bromo-2-chloro-4-fluorobenzene using cuprous bromide.
The literature for direct process of preparing 2,4-dihalobromobenzene from haloaniline is sparse.
Therefore, it remains to develop economic and selective process for preparation of a compound of 2,4-dihalobromobenzenes directly from haloanilines.
OBJECT OF THE INVENTION
The object of the present invention is to provide a cost effective, economic and robust process for preparation of dihalobromobenzene.
SUMMARY OF THE INVENTION
In first aspect, the present invention provides a process for preparation of compound of Formula-1,

Formula-1
wherein X is independently selected from F, Cl, Br, I,
comprising the steps:
a) acylation of a compound of Formula-4;

Formula-4
wherein X is independently selected from F, Cl, Br, I,
in presence of a base in a solvent to obtained a reaction mixture;
b) chlorinating the reaction mixture of step a), using sulphuryl chloride or chlorine to obtain a reaction mass comprising a compound of Formula-3;

Formula-3
c) hydrolysis of the compound of Formula-3 with a base to form a reaction mass;
d) reacting the reaction mass of step c) with an acid to form an acid addition salt of the compound of formula-2;

Formula-2
wherein X represents to; Cl, F, or Br and X? represents HCl, HBr, or H2SO4,
e) converting acid addition salt of Formula-2 to a compound of Formula-1.
In second aspect, the present invention provides a process for the preparation of compound of Formula-1 from compound of Formula-2.
comprising bromination of a compound of Formula-2;

Formula-2
wherein X represents to; Cl, F, or Br and X? represents HCl, HBr, or H2SO4,
with source of nitrite, cuprous bromide and hydrobromic acid to form a compound of Formua-1;

Formula-1

In third aspect, the present invention provides a compound of Formula-2;

Formula-2
wherein X represents to; Cl, F, or Br and X? represents HCl, HBr, or H2SO4,
having purity greater than 98% or preferably greater than 99.5%.

DESCRIPTION OF THE INVENTION
As used herein, term “acylation”, refers to addition of an acyl group to a compound using acylating agent, such as acyl halides. The acylation reaction of the present invention is carried out at a temperature range of 0-30°C, or most preferably carried out at a temperature range of 10-20°C.
As used herein, the “base”, is selected from inorganic base, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and ammonia or mixture thereof.
As used herein, the term “halo” refers to the compound with a halogen group selected from fluorine, chlorine, bromine and iodine.
A solvent used in the step of acylation is selected from a group consisting of chlorinated solvent such as dichloromethane, carbon tetrachloride, chloroform or the like. The step of acylation can be carried out with or without isolation of acylated intermediate.
As used herein, the step of chlorination is carried out using sulphuryl chloride or any chlorinating agent optionally in presence of catalyst. The step of chlorination may be carried with or without isolation of the intermediate of formula-3. The step of chlorination is followed by passing of inert gas such as nitrogen in the reaction mixture. The inert gas enables removal of hydrochloric acid from the reaction mixture, which if left unattended inside the reaction mixture corrodes the product and reduces the yield and purity of the final halobenzene.
Conversion of compound of Formula-3 to compound of Formula-2 in presence of base and a solvent. The solvent is selected from water, methanol, ethanol, isopropanol, tertiary butanol, pentanol, acetonitrile, tetrahydrofuran, or the like. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or the like or a mixtures thereof.
As used herein, an “acid”, is selected from the group consisting of hydrogen chloride, hydrogen iodide, hydrogen fluoride, sulphuric acid, nitric acid or a mixture thereof.
In an embodiment of present invention, the process of hydrolysis is followed in-situ by isolation of acid addition salt of compound of formula-2.
In a preferred embodiment, the present invention is carried out in situ without isolation of the intermediates other than the acid addition salt of the compound of formula-2. The isolation of the acid addition salts of the compound of formula-2 enables high purity of the final halobenzene.
The source of nitrite is selected from the group consisting of sodium nitrite, potassium nitrite, t-butyl nitrite or n-butyl nitrite.
The step of reacting a compound of formula-2 with hydrobromic acid is carried out in presence of sulphuric acid.
The bromination reaction of the present invention may optionally be carried out in presence of a solvent at a temperature selected from at 55 to 60°C.
The bromination reaction of the present invention is carried out in a solvent selected from a group consisting of water, toluene and dichloromethane or a mixture thereof.
In an embodiment, the present invention provides a process for the preparation of 1-bromo-4-chloro-2-fluorobenzene
comprising the steps;
a) acylation of 2-fluoroaniline in the presence of a base in a solvent to obtain a reaction mixture;
b) chlorination of the reaction mixture of step a), using sulphuryl chloride to obtain a reaction mass comprising N-(4-chloro-2-fluorophenyl)acetamide;
c) hydrolysis of reaction mixture of step b) comprising N-(4-chloro-2-fluorophenyl)acetamide;
d) reacting step c) with an acid to form acid salt of 4-chloro-2-fluoroaniline;
e) converting acid salt of 4-chloro-2-fluoroaniline to 1-bromo-4-chloro-2-fluoro benzene.
In another embodiment, the present invention provides a process for the preparation of 1-bromo-4-chloro-2-fluorobenzene from acid salt of 4-chloro-2-fluoroaniline, comprising the step of brominating acid salt of 4-chloro-2-fluoroaniline with sodium nitrite and cuprous bromide with hydrobromic acid to form a 1-bromo-4-chloro-2-fluorobenzene.
In another embodiment, the present invention provides sulphuric acid addition salt of 4-chloro-2-fluoroaniline having purity greater than 98% or preferably greater than 99.5%.
In another embodiment, the present invention provides hydrochloride salt of 4-chloro-2-fluoroaniline having purity greater than 98% or preferably greater than 99.5%.
In another embodiment, the present invention provides acetic acid salt of 4-chloro-2-fluoroaniline having purity greater than 98% or preferably greater than 99.5%.
The compound of Formula-4 may be prepared by any method known in the prior art or may be obtained commercially.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Step 1: Process for the preparation of N-(2-fluorophenyl)acetamide
2-Fluoroaniline (75.48g, 0.679mol), dichloromethane (577.1g, 6.78mol) and 20% sodium hydroxide solution (177.5g, 0.88mol) were added sequentially in a reaction vessel and cooled to 20-25°C. Acetyl chloride (61.42g, 0.78mol) was added dropwise to the reaction mass. After completion of reaction, reaction mass was heated to room temperature and layer separated. Organic layer is washed with water, layer separated and kept as such for next reaction.
Step 2: Process for the preparation of N-(4-chloro-2-fluorophenyl)acetamide
Organic layer from step 1 (652.9g, 0.67mol) was added to a reaction vessel and heated to reflux (40°C). Sulphuryl chloride (128.3g, 0.95mol) was added dropwise to the reaction mass under reflux condition. After completion of reaction, ethanol (437.7g, 9.5mol) was added to reaction mass and dichloromethane is removed from the reaction mass.
Step-2B: Preparation of N-(4-chloro-2-fluorophenyl)acetamide
Organic layer from step 1 (652.9g, 0.67mol) was added to a reaction vessel and heated to reflux (40°C). Chlorine (mole ratio 2.5) was passed to the reaction mass under reflux condition. The reaction was monitored by gas chromatography (area%). After completion of reaction, nitrogen was passed for 15 minutes to remove chlorine and hydrogen chloride gas from the reaction mass. Then dichloromethane was boiled off from the reaction mass.
Step 3A: Process for the preparation of sulphuric acid addition salt of 4-Chloro-2-fluoroaniline
To the reaction mixture of step 2, 20% NaOH solution (312.6g, 1.56mol) was added, heated the mass to reflux and maintained at same temperature for complete conversion. After completion of reaction, reaction mass was subjected to vacuum boil off to remove ethanol. To the bottom mass, toluene (400g, 4.3mol) and water (155.3g, 8.63mol) was added. Reaction mass followed by layer separation. Organic layer containing crude mass, is added to a reaction vessel. Sulphuric acid (24.95g, 0.25mol) was added dropwise to the organic layer and heated to 90°C. The reaction mixture was maintained at same condition for 1 hour and filtered to get pure sulphuric acid addition salt of 4-Chloro-2-fluoroaniline.
Step 3B: Process for the preparation of hydrochloric acid addition salt of 4-Chloro-2-fluoroaniline
To the reaction mixture of step 2, 20% sodium hydroxide solution (312.6g, 1.56mol) was added, heated the mass to reflux and was maintained at same temperature for complete conversion. After completion of reaction, reaction mass was subjected to vacuum to remove ethanol. To the bottom mass, toluene (400g, 4.3mol) and water (155.3g, 8.63mol) was added. Reaction mass followed by layer separation. Organic layer containing crude mass, was added to a reaction vessel. Anhydrous hydrochloric acid (0.25mol) was passed to the organic layer and heated to 90°C. The reaction mixture was maintained at same condition for 1 hour and filtered to get pure hydrochloric acid addition salt of 4-chloro-2-fluoroaniline.
Step 4A: Process for the preparation of 1-bromo-4-chloro-2-fluorobenzene
Sulphuric acid addition salt of 4-Chloro-2-fluoroaniline (0.42mol) and water (13.9mol) were added sequentially in a reaction vessel. Sulphuric acid (248.8g, 2.54mol) was added to aqueous mass at room temperature and cooled the mass to 0-5°C using ice bath. Sodium nitrite solution (155.1g, 0.5mol, aqueous 23%) was added dropwise to the mass to form a diazo mass. Diazo mass was added to a mixture of cuprous bromide (24.38g, 0.17mol) and 47% HBr solution (145.8g, 0.84mol) at 55-60°C in a separate vessel. After complete addition, reaction mass was cooled to room temperature. Dichloromethane and water was added to the cooled reaction mass and layer separated. Organic layer was washed with water and concentrated to get crude mass, mass is vacuum distilled to get pure titled compound.
Purity: 99.24%
Step 4B: Process for the preparation of 1-bromo-4-chloro-2-fluorobenzene
Hydrochloric acid addition salt of 4-chloro-2-fluoroaniline (0.42mol) and water (13.9mol) were added sequentially in a reaction vessel. Added sulphuric acid (248.8g, 2.54mol) to aqueous mass at room temperature and cooled the mass to 0-5°C using ice bath. Sodium nitrite solution (155.1g, 0.5mol, aqueous 23%) was added dropwise to the mass to form a diazo mass. Diazo mass was added to a mixture of cuprous bromide (24.38g, 0.17mol) and 47% HBr solution (145.8g, 0.84mol) at 55-60°C in a separate vessel. After complete addition, reaction mass is cooled to room temperature. Dichloromethane and water was added to the cooled reaction mass and layer separated. Organic layer was washed with water and concentrated to get crude mass, mass is vacuum distilled to get pure titled compound.
Purity: 99.5%

WE CLAIM:
1. A process for the preparation of compound of Formula-1,

Formula-1
wherein X is independently selected from F, Cl, Br, I,
comprising the steps:
a) acylation of a compound of Formula-4;

Formula-4
wherein X is independently selected from F, Cl, Br, I,
in presence of a base in a solvent to obtained a reaction mixture;
b) chlorinating the reaction mixture of step a), using sulphuryl chloride or chlorine to obtain a reaction mass comprising a compound of Formula-3;

Formula-3
c) hydrolysis of the compound of Formula-3 with a base to form a reaction mass;
d) reacting the reaction mass of step c) with an acid for form an acid addition salt of the compound of formula-2;

Formula-2
wherein X represents to; Cl, F, or Br and X? represents HCl, HBr, or H2SO4,
e) converting acid addition salt of Formula-2 to a compound of Formula-1.
2. The process as claimed in claim 1, wherein the step e) comprises bromination of a compound of Formula-2 with a source of nitrite and cuprous bromide and hydrobromic acid to form a compound of Formua-1.
3. The process as claimed in previous claims, wherein the compound of formula -1 has a purity ranging between 98% to 99.8%.
4. The process as claimed in claim 1, wherein the step a) is carried out at a temperature range of 10-20°C.
5. The process as claimed in claim 1, wherein the solvent is selected from carbon tetrachloride, dichloromethane, tetrahydrofuran, chloroform, hydrocarbons such as hexanes, benzene or a mixture thereof.
6. The process as claimed in claim 1, wherein the base is selected from inorganic base, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and ammonia or a mixture thereof.
7. The process as claimed in claim 1, wherein the acid used in step d) is selected from hydrogen chloride, hydrogen iodide, hydrogen fluoride, sulphuric acid, nitric acid or a mixture thereof.
8. The process as claimed in claim 2, wherein the ‘source of nitrite’ is selected from the group consisting of sodium nitrite, potassium nitrite, t-butyl nitrite or n-butyl nitrite.