Field of the invention
The present invention provides a process for preparation of haloalkyl amino pyridines of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom.

Background of the invention
The halogen substituted trihalomethyl amino pyridines are important intermediates for preparation of fungicides such as fluazinam. These compounds are also useful in the synthesis of various agrochemicals and medicines.
Various methods are known in the art for preparation of halogen substituted trihalomethyl amino pyridines of formula 1. e.g., U.S. Patent No. 4,349,681 discloses a process for preparation of 2-amino-3-chloro-5-trifluoromethylpyridine by reacting 2, 3-dichloro-5-trifluoromethylpyridine with aqueous ammonia at 100 to 125°C in low yield. Thus, the process is not economic for large scale production.
Chinese Patent No. 102911115 discloses a process for preparation of 2-amino-3-chloro-5-trifluoromethylpyridine by reacting 2,3-dichloro-5-trifluoromethylpyridine with aqueous ammonia at 100°C in presence of a water soluble adjuvants that is usually a solvent like methanol or propanol etc., optionally in the presence of phase transfer catalyst. The use of solvent in the commercial process would unnecessary increase the cost of the operations at larger scale.
Thus there is a need to develop a cost effective and economical process for preparation of halogen substituted trihalomethyl amino pyridines at commercial scales.

Object of the invention
The object of the present invention is to provide a cost effective and economical process for preparation of halogen substituted haloalkyl amino pyridines of formula 1.

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom.

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

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom,
comprising the steps of:
a) contacting a compound of formula 2 with aqueous ammonia to obtain a reaction mixture; and

wherein X is an halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom.
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain the compound of formula 1,
wherein step a) is carried out without using any organic solvent;
wherein step a) is carried out without using any catalyst; and
wherein the compound of formula 1 contains cyano impurity of formula 3 below 0.5%,

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

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom,
comprising the steps of:
a) contacting a compound of formula 2 with aqueous ammonia to obtain a reaction mixture; and

wherein X is an halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom.
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain the compound of formula 1,
wherein step a) is carried out without using any organic solvent and
wherein step a) is carried out without using any catalyst.

Detailed description of the invention
As used herein, the term “absence of solvent” refers to the process in which no solvent is used to aid the reaction.
As used herein, the term “substantially free of cyano impurity” refers to less than 0.5% of cyano impurity in the final compound.
As used herein, the term “contacting” refers to the step of reacting, mixing, stirring or the like.
As used herein, the term “anhydrous ammonia” refers to gaseous ammonia.
As used herein, the group “X” is a halogen selected from fluorine, chlorine, bromine or iodine. The group “X” can be present at any position on the ring such as at position 2-, 3-, 4-, or 6- with respect to the pyridine ring nitrogen.
As used herein, the group “R” represents C1-C3 alkyl group substituted with at least one halogen atom. Preferably, “R” represents C1-C3 alkyl group substituted with at least one fluorine atom.
In an embodiment of the present invention, the pyridine ring can be monosubstituted, disubstituted or trisubstituted by group “X”.
In an embodiment of the present invention, the contacting is carried out at a temperature in the range of 25 to 125°C , preferably in the range of 40-125°C and most preferably in the 50-125°C.
In an embodiment, the present invention is carried out in presence of pressure selected in the range 1-15 bar.
It is observed that pressure during reaction may reaches up to 15 bar, depending upon reaction temperature.
In another embodiment, the present invention may be carried out at atmosphere pressure.
In another embodiment of the present invention, the aqueous ammonia have concentration in the range of 20 to 60% by mass of ammonia.
In another embodiment of the present invention, the amount of anhydrous ammonia ranges from 6 to 16 moles.
In another embodiment of the present invention, the process is carried out in absence of any solvent.
In another embodiment of the present invention, the process is carried out in absence of any catalyst.
In another embodiment of the present invention, the process is carried out in absence of any phase transfer catalyst.
In another embodiment of the present invention, the process results in the formation of the compound of formula 1 substantially free of cyano impurity.
The inventors of the present invention found that the use of anhydrous ammonia along with aqueous ammonia in the preparation of compound of formula 1 helps in lowering the amount of cyano impurity of formula 3.

In an embodiment, the present invention provides a process for preparation of 2-amino-3-chloro-5-trifluoromethylpyridine
comprising the steps of:
a) contacting 2-fluoro-3-chloro-5-trifluoromethylpyridine with aqueous ammonia in absence of a solvent to obtain a reaction mixture;
b) isolating 2-amino-3-chloro-5-trifluoromethylpyridine from reaction mixture of step-a.
In another embodiment, the present invention provides a process for preparation of 2-amino-3-chloro-5-(trifluoromethyl)pyridine
comprising the steps of:
a) contacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous ammonia in absence of a solvent to obtain a reaction mixture; and
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain 2-amino-3-chloro-5-(trifluoromethyl)pyridine.
In another embodiment, the present invention provides a process for preparation of 2-amino-3-chloro-5-(trifluoromethyl)pyridine having less than 0.5% of 6-amino-5-chloronicotinonitrile.
In another embodiment, the present invention provides a process for preparation of 2-amino-6-chloro-5-(trifluoromethyl)pyridine
comprising the steps of:
a) contacting 2,6-dichloro-5-(trifluoromethyl)pyridine with aqueous ammonia in absence of a solvent to obtain a reaction mixture; and
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain 2-amino-6-chloro-5-(trifluoromethyl)pyridine.
In another embodiment, the present invention provides a process for preparation of 2-amino-6-chloro-5-(trifluoromethyl)pyridine having less than 0.5% of 6-amino-2-chloronicotinonitrile.
In another embodiment, the present invention provides a process for preparation of 2-amino-4-chloro-5-(trifluoromethyl)pyridine
comprising the steps of:
a) contacting 2,4-dichloro-5-(trifluoromethyl)pyridine with aqueous ammonia in absence of a solvent to obtain a reaction mixture; and
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain 2-amino-4-chloro-5-(trifluoromethyl)pyridine.

In another embodiment, the present invention provides a process for preparation of 2-amino-4-chloro-5-(trifluoromethyl)pyridine having less than 0.5% of 6-amino-4-chloronicotinonitrile.

In another embodiment, the present invention provides a process for preparation of 2-amino-3,4-dichloro-5-(trifluoromethyl)pyridine
comprising the steps of:
a) contacting 2,3,4-trichloro-5-(trifluoromethyl)pyridine with aqueous ammonia in absence of a solvent to obtain a reaction mixture; and
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain 2-amino-3,4-dichloro-5-(trifluoromethyl)pyridine.

In another embodiment, the present invention provides a process for preparation of 2-amino-3,4-dichloro-5-(trifluoromethyl)pyridine having less than 0.5% of 6-amino-4,5-dichloronicotinonitrile.
In an embodiment, the present invention provides a process for preparation of compound of formula 1 having yield greater than 97%.
In an embodiment, the present invention provides a process for preparation of compound of formula1 having purity greater than 99%.
The compound of the present invention can be isolated using various isolation techniques known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
In an embodiment of the present invention, the isolation is conducted by means of filtration followed by vacuum distillation.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), gas chromatography (GC), liquid chromatography (LC) and alike.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes 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 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 compound of formula 2 which is used herein as starting material can be prepared by any of the methods known in the art i.e., as disclosed in Chinese patent publication no. 106397309 or can be obtained commercially.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLE
Example 1: Preparation of 2-amino-3-chloro-5-trifluoromethylpyridine
30g of 3-chloro-2-fluoro-5-(trifluoromethyl) pyridine and 107 g of aqueous ammonia solution was charged in a Hastelloy autoclave reactor at 30°C. Gradually reaction mass was heated to 80°C and pressure was 4-5 bar at 80°C. The reaction progress was monitored by GC. After reaction, reactor was cooled to 35° to 40°C and pressure was vented to a water scrubber. Reaction mass was filtered and filtered solid was washed with cold water. The wet solid was dried under vacuum to obtain 2-amino-3-chloro-5-trifluoromethylpyridine as a white crystalline solid.
Yield: 99.1%
Purity (by GC area %): >99.5 %

Example 2: Preparation of 2-amino-3-chloro-5-trifluoromethylpyridine
27g of 2, 3-dichloro-5-(trifluoromethyl) pyridine and 56 g of aqueous ammonia solution (24.62 %) was charged in a Hastelloy autoclave reactor at 30°C. To the above reaction mass, 26g of anhydrous ammonia was purged to maintain internal reactor pressure at 3.2 to 3.5 bars at 30-32°C. Gradually reaction mass was heated to 90°C. Reaction progress was monitored by GC. After completion of the reaction, reactor was cooled to 35° to 40°C and ammonia pressure was vented to a water scrubber. Reaction mass was filtered and filtered cake was washed with cold water to obtain wet solid. The wet solid was dried under vacuum to obtain the titled compound i.e., 2-amino-3-chloro-5-trifluoromethylpyridine as a white crystalline solid.
Yield: 97%
Purity (by GC area %): 99.5 %
Cyano impurity by (GC area %): 0.1%.
Example 3: Preparation of 2-amino-6-chloro-5-(trifluoromethyl)pyridine
20g of 2,6-dichloro-5-(trifluoromethyl) pyridine and 42g of aqueous ammonia solution was charged in a Hastelloy autoclave reactor at 30°C. Gradually reaction mass was heated to 80°C and pressure was 4-5 bar at 80°C. The reaction progress was monitored by GC. After reaction, reactor was cooled to 35° to 40°C and pressure was vented to a water scrubber. Reaction mass was filtered and filtered solid was washed with cold water. The wet solid was dried under vacuum to obtain 2-amino-3-chloro-5-trifluoromethylpyridine as a white crystalline solid.
Yield: 96%
Purity (by GC area %): >99.5 %

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

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom,
comprising the steps of:
a) contacting a compound of formula 2 with aqueous ammonia to obtain a reaction mixture; and

wherein X is an halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom.
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain the compound of formula 1,
wherein step a) is carried out without using any organic solvent;
wherein step a) is carried out without using any catalyst; and
wherein the compound of formula 1 contains cyano impurity of formula 3 below 0.5%,

wherein X is an halogen selected from chlorine, bromine, iodine and fluorine.

2. A process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom,
comprising the steps of:
a) contacting a compound of formula 2 with aqueous ammonia to obtain a reaction mixture; and

wherein X is an halogen selected from chlorine, bromine, iodine and fluorine and R represents C1-C3 alkyl group substituted with at least one halogen atom.
b) adding anhydrous ammonia to the reaction mixture of step a) to obtain the compound of formula 1,
wherein step a) is carried out without using any organic solvent and
wherein step a) is carried out without using any catalyst.

3. The process as claimed in claim 1, wherein the compound of formula 1 contains cyano impurity of formula 3 below 0.2%.

4. The process as claimed in claim 1, wherein the compound of formula 1 contains cyano impurity of formula 3 below 0.1%.

5. The process as claimed in claim 1 and 2, wherein the concentration of aqueous ammonia is selected in the range of 20 to 60% by mass of ammonia.

6. The process as claimed in claim 1 and 2, wherein the moles of anhydrous ammonia is selected in the range of 6 to 16.

7. The process as claimed in claim 1 and 2, wherein the compound of formula 1 is prepared at a temperature selected in the range of 80 to 125°C.

8. The process as claimed in claim 1 and 2, wherein the compound of formula 1 is prepared at a temperature selected in the range of 10 to 30 bar.