Field of the Invention
The present invention relates to a process for fluorination of aromatic compounds of Formula IV.

Formula IV
Background of the Invention
The di-substituted aromatic fluoro compounds of Formula III are important intermediates for preparation of agrochemicals and pharmaceutical compounds.

Formula III
The EP Patent No. 0,734,363 B1 describes a process for fluorination of di-substituted aromatic compounds using fluorine gas in the presence of an acid such as formic acid.
The present inventors observed that fluorination of di-substituted aromatic compounds using hydrogen fluoride, optionally, in the presence of amines, provides a simple, cost effective, selective and industrially favorable process for the preparation of di-substituted aromatic fluoro compounds.

Object of the invention
The main object of the present invention is to provide a simple, cost effective, selective and industrially favorable process for preparation of di-substituted aromatic fluoro compounds of Formula III.

Summary of the Invention
The present invention provides a process for preparation of compound of Formula III, comprising;
a) contacting hydrogen fluoride with compound of Formula IV, optionally in the presence of HF complexing agent to obtain a mixture,
b) contacting step a) mixture with sodium nitrite to obtain compound of Formula III, and

Formula III Formula IV
c) isolating compound of Formula III from step b).
Detailed Description of the Invention
The term ‘about’ refers to a variation of 10% on the higher and lower side of specified parameter.
The present invention provides a process for preparation of compound of Formula III, comprising;
a) contacting hydrogen fluoride with compound of Formula IV, optionally in the presence of HF complexing agent to obtain a mixture,
b) contacting step a) mixture with sodium nitrite to obtain compound of Formula III, and

Formula III Formula IV
c) isolating compound of Formula III from step b).

In particular, the present invention provides a process for preparation of compound of Formula I, comprising;
a) contacting hydrogen fluoride with compound of Formula II, optionally in the presence of HF complexing agent to obtain a mixture,
b) contacting step a) mixture with sodium nitrite to obtain compound of Formula I, and

Formula I Formula II
c) isolating compound of Formula I from step b).
The hydrogen fluoride (HF) used as a fluorinating agent is in liquid form.
The step a) may take place at a temperature range of -100oC to 40oC for about 5 minutes to about 3 hours.
The step of contacting sodium nitrite with step a) mixture is done in a lot-wise manner. Upon contacting sodium nitrite with step a) mixture, the mixture may be taken in pressure reactor and stirred at 4-5 kg/cm2. The temperature during stirring may be maintained in the range of -10oC to 90oC for about 5 minutes to about 3 hours.
The HF complexing agent used in step a) is selected from a group consisting of amines preferably aliphatic and aromatic amines, ethers preferably dialkyl ethers and cyclic ethers, dimethylsufoxide, urea, glyme, acetonitrile, dimethylacetamide, dimethylformamide, dimethylsulfone and sulfolane.
The aliphatic and aromatic amines are selected from a group represented by the Formula X.

wherein
R1, R2 and R3 is independently selected from C1 to C10 alkyl, cyclo alkyl, aryl, substituted aryl, hetero aryl and substituted hetro aryl;
R2 and R3 together with the nitrogen form an aliphatic ring or
R2 and R3 together with the nitrogen form a hetero aromatic ring provided R1 is absent.
The preferred aliphatic amines are selected from the group consisting of methyl cyclo hexyl amine, N-methyl piperidine, trimethyl amine, triethylamine, di-isopropylethylamine, tripropylamine, diphenylmethyl amine, phenyl dimethyl amine, diphenylethylamine, phenyl diethyl amine, dimethyl ethylamine, diethylmethylamine and the like.
The preferred aromatic amines are selected from the group consisting of pyridine and derivatives thereof, pyrimidine and derivatives thereof, pyrazine and derivatives thereof, pyridazine and derivatives thereof, triazine or its isomers and derivatives thereof, N, N-disubstituted anilines, N-substituted pyrrole and derivatives thereof.
In a preferred embodiment, the HF complexing agent is generated in-situ in the reaction mixture.
In another preferred embodiment, the HF complexing agent is pyridine:HF generated in-situ in the reaction using pyridine and HF.
The compound of Formula III is isolated by any method known in the art, for example, chemical separation, acid-base neutralization, distillation, evaporation, column chromatography and filtration or mixture thereof.
The starting materials i.e. the compounds of formula IV are commercially available.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

Examples
Example: 1 Preparation of 3-fluoro-4-methylbenzonitrile in absence of amine
3-amino-4-methylbenzonitrile (1 mol) was charged into the metal reactor followed by anhydrous hydrogen fluoride (22 mol) at -20oC. 1.2 mol of sodium nitrite was added in lot wise manner and the mixture was allowed to be at 5-10°C. The reaction was stirred for 1 hour.
The above mass was transferred to autoclave and heated to 60-70°C under stirring until the evolution of nitrogen ceased and the mass was cooled to 35-40°C. The pressure released carefully through traps containing water and the mass was extracted with 500 mL of dichloromethane. The dichloromethane layers were combined and washed with 2 X 100mL of water followed by 100 ml of 5% potassium carbonate solution. Dichloromethane layer was concentrated under reduced pressure to dryness. The crude product was purified by crystallization.
Yield: 20%
Purity: 99% (by HPLC)
Example: 2 Preparation of 3-fluoro-4-methylbenzonitrile in presence of amine
Pyridine (1.8 mol) was charged into the autoclave reactor and the reactor was closed and cooled to -50°C. To the cooled reactor, 22 moles of anhydrous hydrogen fluoride was charged. 3-amino-4-methylbenzonitrile (1.0 mol) was added portion wise over the period of 30-45 minutes. The mixture was maintained at 0 to 5°C for 30 minutes. To the resultant mixture, sodium nitrite (1.2 mol) was added lot-wise by maintaining the mass temperature in the range of 0 to 5°C. The reaction mass was further stirred for 60 minutes at 0-5 °C. The reactor slowly heated to 75°C until the evolution of nitrogen ceased and cooling the mass to 35-40°C. Pressure was released carefully through traps containing water and the mass was extracted with 500 mL of dichloromethane. The dichloromethane layers were combined and washed with 2 X 100mL of water followed by 100 mL of 5% potassium carbonate solution. Dichloromethane layer was concentrated under reduced pressure to obtain title product.
Yield: 60%
Purity: 99% (by HPLC)

CLAIMS:

1. A process for preparation of compound of Formula I, comprising;
a) contacting hydrogen fluoride with compound of Formula II, optionally in the presence of HF complexing agent to obtain a mixture,
b) contacting step a) mixture with sodium nitrite to obtain compound of Formula I, and

Formula I Formula II
c) isolating compound of Formula I from step b).
2. A process for preparation of compound of Formula III, comprising;
a) contacting hydrogen fluoride with compound of Formula IV, optionally in the presence of HF complexing agent to obtain a mixture,
b) contacting step a) mixture with sodium nitrite to obtain compound of Formula III, and

Formula III Formula IV
c) isolating compound of Formula III from step b).
3. The process as claimed in claim 1 and 2, wherein hydrogen fluoride is in liquid form.
4. The process as claimed in claim 1 and 2, wherein the step a) takes place at a temperature range of -100oC to 40oC.
5. The process as claimed in claim 1 and 2, wherein the step b) takes place at a temperature range of -10oC to 90oC.
6. The process as claimed in claim 1 and 2, wherein the step a) takes place in presence of HF complexing agent selected from a group consisting of amines preferably aliphatic and aromatic amines, ethers preferably dialkyl ethers and cyclic ethers, dimethylsufoxide, urea, glyme, acetonitrile, dimethylacetamide, dimethylformamide, dimethylsulfone and sulfolane.
7. The process as claimed in claim 6, wherein the aliphatic and aromatic amines are selected from a group represented by the Formula X.

wherein,
R1, R2 and R3 is independently selected from C1 to C10 alkyl, cyclo alkyl, aryl, substituted aryl, hetero aryl and substituted hetro aryl;
R2 and R3 together with the nitrogen form an aliphatic ring or
R2 and R3 together with the nitrogen form a hetero aromatic ring provided R1 is absent.
8. The process as claimed in claim 7, wherein the preferred aliphatic amines are selected from the group consisting of methyl cyclohexyl amine, N-methyl piperidine, trimethyl amine, triethylamine, di-isopropylethylamine, tripropylamine, diphenylmethyl amine, phenyl dimethyl amine, diphenylethylamine, phenyl diethyl amine, dimethyl ethylamine and diethylmethylamine or mixture thereof.
9. The process as claimed in claim 8, wherein the preferred aromatic amines are selected from the group consisting of pyridine and derivatives thereof, pyrimidine and derivatives thereof, pyrazine and derivatives thereof, pyridazine and derivatives thereof, triazine or its isomers and derivatives thereof, N, N-disubstituted anilines, N-substituted pyrrole and derivatives thereof.