Field of the Invention
The present invention relates to a process for preparation of halo substituted alkanes.

Background of the invention
Halo substituted alkanes are useful intermediates in pharmaceuticals and agrochemical industry. Halo substituted alkanes can also be used with special advantage as heat transfer agents and have acquired importance for the manufacture of narcotics.

The present invention relates to a process for preparation of halo substituted alkanes.
Several methods are known for preparation of halo substituted alkanes. Great Britain Patent No. 1012797 provides a process for preparation of a haloalkanes containing at least one bromine atom and at least one fluorine atom. The preparation involves reaction of alkene with hydrogen bromide in the liquid phase under radical-forming conditions and isolating the halo-alkane so obtained.

PCT Publication No. 2009/040367 provides a process for preparation of 2-bromo-1, 1-difluoroethane by contacting vinylidene difluoride and hydrogen bromide in presence of ultra violet light at ambient pressure and temperature.

PCT Publication No. 2016/105907 provides a method of making a halogenated partially fluorinated compound, by reacting hydrocarbon olefin with an iodine or bromine containing salt selected from alkaline halogenides, alkaline earth halogenides, and tetraalkylammonium halogenides in the presence of an acid to form the halogenated partially fluorinated compounds.

Thus all the processes provided in the prior art involves addition of bromine to alkenes and thus suffer from several disadvantages, for example, formation of undesired addition products, which results in low yield and purity and makes the process uneconomical. Also, the use of ultra violet light for irradiating alkene for bromination is not industrially viable.

Thus, there is an urgent need to develop a robust process for preparation of halo substituted alkanes which results in high yield, purity and is industrially safe and economic.

Summary of the invention
The present invention provides a process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 2 with a brominating agent to obtain a compound of formula 1, and

Formula-2
b) isolating the compound of formula 1 obtained from step a),
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H;
X4 is selected from Cl, I and F.
The present invention also provides a process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 3 with a source of nitrite and acid to obtain a mixture,

Formula-3
b) contacting brominating agent with the mixture of step a) to obtain a compound of formula 1, and
c) isolating the compound of formula 1 obtained from step b).
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H.

The present invention further provides a process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 3 with a source of nitrite and hydro bromic acid to obtain a compound of formula 1, and

Formula-3
b) isolating the compound of formula 1 obtained from step a).
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H.

Object of the Invention
The main object of the present invention is to provide a simple, cost effective and industrially applicable process for preparation of halo substituted alkanes.

Detailed description of the invention
In one aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 2 with a brominating agent to obtain a compound of formula 1, and

Formula-2
b) isolating the compound of formula 1 obtained from step a),
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H;
X4 is selected from Cl, I and F.

An embodiment of this aspect of the present invention provides a process for preparation of a compound of formula 1a,

Formula-1a
comprising:
a) contacting a compound of formula 2a with a brominating agent to obtain a compound of formula 1a, and

Formula-2a
b) isolating the compound of formula 1a obtained from step a),
In this aspect of the invention, the step a) may be carried out at a temperature selected from 70°C to 250°C for about 2 hours to 20 hours and at a pressure selected from 0 to 15 bar.
The step a) may be carried out in presence or absence of a polar organic solvent selected from the group consisting of N, N dimethyl formamide, sulfolane, N, N dimethylacetamide, N-methyl-2- pyrolidone, dimethyl sulfoxide, acetamide and the like.

The step a) may optionally be carried out in presence of a phase transfer catalyst selected from the group consisting of tetra butyl ammonium bromide, tetra butyl ammonium chloride and tetraphenylphosphonium bromide or the like.
The process of step a) and step b) may be carried out in batch reactor mode or continuous reactor mode.
In the continuous rector mode, the unreacted 2-chloro-1, 1-fluoro ethane is recycled back to the reactor.

In second aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 3 with a source of nitrite and acid to obtain a mixture,

Formula-3
b) contacting brominating agent with the mixture of step a) to obtain a compound of formula 1, and
c) isolating the compound of formula 1 obtained from step b).
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H.

An embodiment of this aspect of the present invention provides a process for preparation of compound of formula 1a,

Formula-1a
comprising:
a) contacting a compound of formula 3a with a source of nitrite and acid to obtain a mixture,

Formula-3a
b) contacting brominating agent with the mixture of step a) to obtain a compound of formula 1a, and
c) isolating the compound of formula 1a obtained from step b).
In third aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 3 with a source of nitrite and hydro bromic acid to obtain a compound of formula 1, and

Formula-3
b) isolating the compound of formula 1 obtained from step a).
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H.

An embodiment of this aspect of the present invention provides a process for preparation of compound of formula 1a,

Formula-1a
comprising:
a) contacting a compound of formula 3a with a source of nitrite and hydro bromic acid to obtain a compound of formula 1a, and

Formula-3a
b) isolating the compound of formula 1a obtained from step a).

In first and second aspect of the present invention, the brominating agent used for bromination is selected from the group consisting of sodium bromide, potassium bromide, lithium bromide, rubidium bromide, benzyltrimethylammonium tribromide, boron tribromide, n-bromoacetamide, bromodimethylsulfonium bromide, n-bromophthalimide, n-bromosaccharin, n-bromosuccinimide, bromotrichloromethane, 1-butyl-3-methylimidazolium tribromide, carbon tetrabromide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, 5,5-dibromomeldrum's acid, 1,2-dibromo-1,1,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, monosodium bromoisocyanurate hydrate, phosphorus tribromide, pyridinium bromide perbromide, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, hydrogen bromide and bromine or a mixture thereof.

The acid used in second aspect is selected from the group consisting of hydrogen chloride, hydrogen iodide, hydrogen fluoride, acetic acid, phosphoric acid, nitric acid, para-toluene sulfonic acid, sulfuric acid and perchloric acid or a mixture thereof.

The source of nitrites as used in second and third aspect is selected from the group consisting of sodium nitrite, potassium nitrite, silver nitrite, ammonium nitrite, calcium nitrite, lithium nitrite, amyl nitrite, isopentyl nitrite, cyclohexyl nitrite, ethyl nitrite, hexyl nitrite, isobutyl nitrite, 2-methylpropyl nitrite, isopropyl nitrite, methyl nitrite, n-butyl nitrite, pentyl nitrite, tert-butyl nitrite and nickel(ii)nitrite or the mixture thereof.

The bromination reaction of second and third aspect of the present invention may optionally be carried out in presence of a solvent at a temperature selected from -5°C to 50°C for about 1 hours to 6 hours.
In second and third aspect of the present invention, the solvent used may be water, polar protic solvents selected from methanol, ethanol, t-butanol, acetic acid, isopropanol and n-propanol or a mixture thereof.

Further the bromination reaction of second and third aspect of the present invention, may optionally be carried out in presence of a catalyst selected from the group consisting of copper(I) bromide, copper(II) bromide, copper(I) chloride, copper(II) chloride, copper(I) iodide, copper(II) iodide, copper(I) sulfate, copper(II) sulfate, copper(II) sulfate pentahydrate or the mixture thereof.

The compound of formula-1 is isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.

The compound of formula-1 so obtained by the present invention have a purity, greater than 95 %, more preferably greater than 98 %, most preferably greater than 99%.

Unless stated to the contrary, any of the words “comprising” and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.

The compounds of formula-2 and formula-3 may be prepared by any method known in the prior art or can be obtained commercially.

Preparation of 2-bromo-1, 1-difluoroethane from 2-chloro-1, 1-difluoroethane.
Example 1: The potassium bromide (568.4g, 4.77 mole), sulfolane (909.7g, 7.54 mole), tetrabutylammonium bromide (3.84g, 0.011 mole) and 2-chloro-1, 1-difluoroethane (120g, 1.99 mole) were taken into a reaction vessel and heated at 175-180°C for 8 hours. Progress of reaction was monitored by gas chromatography. The 2-bromo-1, 1-difluoroethane thus obtained was isolated from reaction mixture by distillation under vacuum and unreacted 2-chloro-1, 1-difluoroethane was recycled into reaction vessel as a starting material for the next cycle. The 2-bromo-1, 1-difluoroethane was fractionally distilled to get pure 2-bromo-1, 1-difluoroethane.
Analysis:
2-bromo-1, 1-difluoroethane Conversion per cycle: 44.2%
Selectivity: 95.25%
Purity: 99.67% (by gas chromatography)

Example 2: The sulfuric acid (1.81g) was taken into a reaction vessel and temperature was maintained between 0-5°C. The 2, 2-difluoroethylamine (1g) was added to the above reaction vessel and stirred for half an hour. The aqueous solution of sodium nitrite (0.89g) was added dropwise at temperature between 0-5°C and stirred for half an hour. The aqueous solution of hydrogen bromide (6.4g, 47%) and copper(II) sulfate pentahydrate (3.07g) were simultaneously added at -5° to 50°C and stirred for another one hour at -5° to 50°C to obtain the 2-bromo-1, 1-difluoroethane.
Analysis:
2-bromo-1, 1-difluoroethane Conversion: 100%
Selectivity: 21.3% (by gas chromatography)

WE CLAIM:
1. A process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 2 with a brominating agent to obtain a compound of formula 1, and

Formula-2
b) isolating the compound of formula 1 obtained from step a),
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H;
X4 is selected from Cl, I and F.
2. A process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 3 with a source of nitrite and acid to obtain a mixture,

Formula-3
b) contacting brominating agent with the mixture of step a) to obtain a compound of formula 1, and
c) isolating the compound of formula 1 obtained from step b).
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H.
3. A process for preparation of a compound of formula 1,

Formula-1
comprising:
a) contacting a compound of formula 3 with a source of nitrite and hydro bromic acid to obtain a compound of formula 1, and

Formula-3
b) isolating the compound of formula 1 obtained from step a).
wherein X1, X2 and X3 are selected from Cl, Br, I , F and H provided that atleast one of X1, X2 and X3 is H.
4. The process as claimed in claim 1 and 2, wherein the brominating agent is selected from the group consisting of sodium bromide, potassium bromide, lithium bromide, rubidium bromide, benzyltrimethylammonium tribromide, boron tribromide, n-bromoacetamide, bromodimethylsulfonium bromide, n-bromophthalimide, n-bromosaccharin, n-bromosuccinimide, bromotrichloromethane, 1-butyl-3-methylimidazolium tribromide, carbon tetrabromide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, 5,5-dibromomeldrum's acid, 1,2-dibromo-1,1,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, monosodium bromoisocyanurate hydrate, phosphorus tribromide, pyridinium bromide perbromide, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, hydrogen bromide and bromine or a mixture thereof.
5. The process as claimed in claim 1, wherein the step a) is carried out in presence of a phase transfer catalyst selected from the group consisting of tetra butyl ammonium bromide, tetra butyl ammonium chloride and tetraphenylphosphonium bromide.
6. The process as claimed in claim 2, wherein the acid used is selected from the group consisting of hydrogen chloride, hydrogen iodide, hydrogen fluoride, acetic acid, phosphoric acid, nitric acid, para-toluene sulfonic acid, sulfuric acid and perchloric acid or a mixture thereof.
7. The process as claimed in claim 2 and 3, wherein the source of nitrite is selected from the group consisting of sodium nitrite, potassium nitrite, silver nitrite, ammonium nitrite, calcium nitrite, lithium nitrite, amyl nitrite, isopentyl nitrite, cyclohexyl nitrite, ethyl nitrite, hexyl nitrite, isobutyl nitrite, 2-methylpropyl nitrite, isopropyl nitrite, methyl nitrite, n-butyl nitrite, pentyl nitrite, tert-butyl nitrite and nickel(ii)nitrite or the mixture thereof.
8. The process as claimed in claim 2 and 3, wherein the bromination reaction is carried out in presence of a catalyst selected from the group consisting of copper(I) bromide, copper(II) bromide, copper(I) chloride, copper(II) chloride, copper(I) iodide, copper(II) iodide, copper(I) sulfate, copper(II) sulfate, copper(II) sulfate pentahydrate or a mixture thereof.
9. The process as claimed in claim 1, wherein the step a) is carried out in presence of a polar organic solvent selected from the group consisting of N, N dimethyl formamide, sulfolane, N, N dimethylacetamide, N-methyl-2- pyrolidone, dimethyl sulfoxide, acetamide and a mixture thereof.
10. The process as claimed in claim 2 and 3, wherein the bromination reaction is carried out in presence of water or polar protic solvents selected from methanol, ethanol, t-butanol, acetic acid, isopropanol and n-propanol or a mixture thereof.

Dated this 23rd day of December 2016

Kapil
Research Associate (IPR)
SRF Limited