The present invention provides a process for preparation of substituted aminopyridines of formula 1,

Formula 1
wherein X and X1 are independently selected from a halogen, R is independently selected from hydrogen or C1-C3 alkyl; n ranges from 0-3.

BACKGROUND OF THE INVENTION
The halogen substituted trihalomethyl aminopyridines 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 aminopyridines.
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 for more than 20 hours. The process involves multiple extraction and distillations to obtain product as a viscous liquid that need further purification.
PCT No. 2011092618 provides a process for preparation of 2-amino-3-chloro-5-trifluoromethylpyridine by reacting 2-fluoro-3-chloro-5-trifluoromethylpyridine with anhydrous ammonia in an organic solvent such as tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide and N-methyl-2-pyrrolidone.
Journal of Fluorine Chemistry, 1999, 93,153-157 provides a process for preparation of substituted aminopyridines from halo-substituted pyridine using ammonia at 170-380°C.
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 an adjuvants like methanol or propanol.
The processes available in literature use solvents, adjuvants or phase transfer catalyst that would unnecessary increase the cost of operations at larger scale.
Thus, there is a need to develop a cost effective and economical process for preparation of halogen substituted trihalomethyl aminopyridines 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 substituted aminopyridines of formula 1.

Formula 1
wherein X and X1 are independently selected from a halogen, R is independently selected from hydrogen or C1-C3 alkyl; n ranges from 0-3.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula 1
wherein X and X1 are independently selected from a halogen, R is independently selected from hydrogen or C1-C3 alkyl; n ranges from 0-3,
comprising the step of reacting a compound of formula 2,

Formula 2
wherein L is a leaving group, X and X1 are independently selected from a halogen, n ranges from 0-3
with (R)2NH, wherein R is independently selected from hydrogen or C1-C3 alkyl; to obtain the compound of formula 1.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “leaving group” is selected from halogen, or mesylate, tosylate or the like.
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 ring nitrogen. The preferred position is 3- with respect to the ring nitrogen.
The CX13- can be present at ortho-, meta- or para to ring nitrogen and preferred position are meta- and para- to the ring nitrogen and is selected from CClF2, CCl2F, CF3, CCl3 or the like. It is further provided that when L is chloro, then CX13 is either CF2Cl, or CFCl2.
As used herein, “amination” refers to the process of reacting a compound of formula 2 with a solution (R)2NH or a compound of formula (R)2NH.
As used herein, “R” is a hydrogen or C1-C3 alkyl group. The C1-C3 alkyl group is selected from methyl, ethyl, propyl, isopropyl or the like.
As used herein, (R)2NH may be selected from ammonia, methylamine, ethylamine, dimethylamine, diethylamine, propylamine, isopropylamine or like.
The solution of (R)2NH refers to an aqueous or organic solution.
In an embodiment of present invention, an aqueous solution of (R)2NH is used for amination of compound of formula 2, wherein amination is carried out in absence of organic solvent.
In another embodiment, a solution of (R)2NH refers to an organic solution and organic solvent is selected from alcohols such as methanol, ethanol, isopropanol, propanol, butanol or pentanol or like; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; amines such as n-methyl-pyrrolidone, trimethylamine, tripropylamine or like. The organic solvent is used in very limited quantity for present invention.
The solution of (R)2NH have concentration in the range of 20 to 70 % by mass of (R)2NH and more preferably in the range of 25-40 %.
In another embodiment, the present invention provides a process for preparation of a compound of formula 1,

Formula 1
wherein X and X1 are independently selected from a halogen, R is independently selected from C1-C3 alkyl; n ranges from 0-3,
comprising the step of reacting a compound of formula 2, with a compound of formula (R)2NH, wherein R is independently selected from C1-C3 alkyl; to obtain the compound of formula 1.
The process may be carried out in presence of solvent selected from water, alcohols such as methanol, ethanol, isopropanol, propanol, butanol or pentanol or like; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; amines such as n-methyl-pyrrolidone, trimethylamine, tripropylamine or like.
In an embodiment, the present invention provides a process for preparation of compound of formula 1, by continuously adding a compound of formula (R)2NH, to a reaction mixture containing a compound of formula 2 and solvent , wherein R is not hydrogen.
In an embodiment of the present invention, the amination is carried out at a temperature in the range of 25 to 120°C, preferably in the range of 30-90°C and most preferably in the 40-80°C.
In an embodiment, amination take place in 2-8 hours and more preferably 2-5 hours. The short reaction time is advantageous in achieving high yield and prevent impurity formation under pressure.
In an embodiment, the present invention is carried out in presence of pressure selected in the range 1-12 bar.
In another embodiment, the present invention may be carried out at atmosphere pressure. The reaction hours of process will increase, when reaction is carried out at low temperature and atmospheric pressure.
In an embodiment of the present invention, the molar ratio of (R)2NH is used in the range from 2 to 15 moles and more preferably 5 to 12 moles.
In preferred embodiment, the process is using 28 % aqueous ammonia solution.
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 an embodiment, the present invention provides a process for preparation of 2-amino-3-chloro-5-trifluoromethylpyridine comprising the steps of reacting 2-fluoro-3-chloro-5-trifluoromethylpyridine with aqueous ammonia in absence of organic solvent.
In another embodiment, the present invention provides a process for preparation of 2-amino-3-chloro-5-trifluoromethylpyridine from 2-fluoro-3-chloro-5-trifluoromethylpyridine with aqueous ammonia in absence of phase transfer catalyst.
In an embodiment, the present invention provides a process for preparation of 2-amino-4-chlorodifluromethylpyridine comprising the steps of reacting 2-chloro-4-chlorodifluromethylpyridine with aqueous ammonia in absence of organic solvent.
In another embodiment, the present invention provides a process for preparation of 2-amino-4-trifluoromethylpyridine from 2-fluoro-4-trifluoromethylpyridine with aqueous ammonia in absence of water soluble adjuvants.
In an embodiment, the present invention provides a process for preparation of 2-amino-6-chloro-4-trifluoromethylpyridine comprising the steps of reacting 2,6-dichloro-4-trifluoromethylpyridine with aqueous ammonia in absence of water soluble adjuvants.
In an embodiment, the present invention provides a process for preparation of 2-amino-6-chloro-4-trifluoromethylpyridine comprising the steps of reacting 2,6-dichloro-4-trifluoromethylpyridine with aqueous ammonia in absence of organic solvent.
In an embodiment, the present invention provides a process for preparation of 2-amino-6-chloro-4-trifluoromethylpyridine comprising the steps of reacting 2,6-dichloro-4-trifluoromethylpyridine with aqueous ammonia in absence of phase transfer catalyst.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-methyl-5-(trifluoromethyl)-2-pyridinamine comprising the steps of reacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous methylamine in absence of water soluble adjuvants.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-methyl-5-(trifluoromethyl)-2-pyridinamine comprising the steps of reacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous methylamine in absence of organic solvent.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-methyl-5-(trifluoromethyl)-2-pyridinamine comprising the steps of reacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous methylamine in absence of phase transfer catalyst.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-ethyl-5-(trifluoromethyl)-2-pyridinamine comprising the steps of reacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous ethylamine in absence of phase transfer catalyst.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-ethyl-5-(trifluoromethyl)-2-pyridinamine comprising the steps of reacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous ethylamine in absence of organic solvent.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-ethyl-5-(trifluoromethyl)-2-pyridinamine comprising the steps of reacting 2,3-dichloro-5-(trifluoromethyl)pyridine with aqueous ethylamine in absence of water soluble adjuvants.
In an embodiment, the present invention provides a process for preparation of 3-chloro-N-ethyl-5-(trifluoromethyl)-2-pyridinamine comprising continuously adding anhydrous ethylamine in a reaction mass containing 2,3-dichloro-5-(trifluoromethyl)pyridine in ethanol.
In another embodiment, the present invention provides a process for preparation of Fluazinam by coupling of 2-amino-3-chloro-5-trifluoromethylpyridine obtained by the present process, with 2,4-dichloro-3,5-dinitro-benzotrifluoride to obtain the fungicide Fluazinam.
In one embodiment, reaction mixture was filtered and isolated a compound of formula 1.
In another embodiment, reaction mixture is extracted using a solvent and concentrated to isolate a compound of formula 1.
The solvent for isolation may be selected from a group consisting of halogenated hydrocarbons, esters and ethers. The halogenated hydrocarbon are dichloromethane, dichloroethane, chloroform, tetrachloromethane, esters are methyl acetate, ethyl acetate, propyl acetate and ethers are diethyl ether, dimethyl ether, tert-butyl methyl ether, dioxane or like.
In an embodiment, optionally, a compound of formula 1 is recrystallized in hexane.
In an embodiment, the present invention provides a process for preparation of a compound of formula 1, is having purity greater than 99 %.
In an embodiment, the present invention provides a process for preparation of compound of formula 1 having yield greater than 85 % and more preferably greater than 90 %.
The compound of formula 1 may refer to a compound selected from 2-amino-3-chloro-5-trifluoromethylpyridine, 2-amino-4-trifluoromethylpyridine, 2-amino-6-trifluoromethylpyridine, 2-amino-3-chloro-6-trifluoromethylpyridine, 2-amino-3-chloro-5-chlorodifluoromethylpyridine, 2-amino-4-dichlorofluoromethylpyridine, 2-amino-6-chlorodifluoromethylpyridine, 2-amino-6-chloro-4-trifluoromethylpyridine, 2-amino-3-chloro-6-chlorodifluoromethylpyridine, 3-chloro-N-methyl-5-(trifluoromethyl)-2-pyridinamine, 3-chloro-N-ethyl-5-(trifluoromethyl)-2-pyridinamine, 3-chloro-N,N-diethyl-5-(trifluoromethyl)-2-pyridinamine, 3-chloro-N-propyl-5-(trifluoromethyl)-2-pyridinamine, 3-chloro-N,N-dipropyl-5-(trifluoromethyl)-2-pyridinamine, 3-chloro-N-ethyl-N-methyl-5-(trifluoromethyl)-2-pyridinamine, N-methy-4-trifluoromethyl-2-pyridinamine, N-methyl-6-trifluoromethyl-2-pyridinamine, N-ethyl-6-trifluoromethyl-2-pyridinamine, 3-chloro-N-methyl-6-trifluoromethyl-2-pyridinamine, 3-chloro-N-methyl-6-chlorodifluoromethyl-2-pyridinamine, N-methy-5-trifluoromethyl-2-pyridinamine or the like.
The compound of formula 2 may refer to a compound selected from 2-fluoro-3-chloro-5-trifluoromethylpyridine, 2-fluoro-4-trifluoromethylpyridine, 2-fluoro-6-trifluoromethylpyridine, 2-fluoro-3-chloro-6-trifluoromethylpyridine, 2,3-dichloro-5-chlorodifluoromethylpyridine, 2,3-dichloro-5-trifluoromethylpyridine, 2-fluoro-4-dichlorofluoromethylpyridine, 2-fluoro-4-chlorodifluoromethylpyridine, 2-fluoro-6-chlorodifluoromethylpyridine, 2-fluoro-3-chloro-6-chlorodifluoromethylpyridine, 2,6-dichloro-4-trifluoromethylpyridine and 2,3-dichloro-6-chlorodifluoromethylpyridine or like.
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.
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 methods known in the art.
The solution of (R)2NH used for present invention may be prepared or 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.

EXAMPLES
Example 1: Preparation of 2-amino-3-chloro-5-trifluoromethylpyridine
3-chloro-2-fluoro-5-trifluoromethylpyridine (30 g) and aqueous ammonia solution (107 g; 25 %) were charged in a Hastelloy autoclave reactor at 30°C. The reaction mass was heated to a temperature of 80°C and a pressure of 4-5 bar. The progress of reaction 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
3-chloro-2-fluoro-5-trifluoromethylpyridine (30 g) and aqueous ammonia solution (36.5 g; 28 %) were charged in a Hastelloy autoclave reactor at room temperature. The reaction mass was gradually reaction mass heated to a temperature of 80°C and pressure of 3-5 bar. 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: 98 %;
Purity (by GC area %): 99.4 %
Example 3: Preparation of 2-amino-3-chloro-5-trifluoromethylpyridine
3-chloro-2-fluoro-5-trifluoromethylpyridine (30 g) and aqueous ammonia solution (107 g; 25 %) were charged in a Hastelloy autoclave reactor at 30°C. The reaction mass was gradually heated to a temperature of 50°C and pressure of 1-3 bar. The reaction progress was monitored by GC. After reaction, reactor was cooled to 35°C 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 %;
Purity (by GC area %): 99 %
Example 4: Preparation of 2-amino-4-chlorodifluoromethyl pyridine
2-fluoro-4-chlorodifluoromethylpyridine (147.0 g, 0.75 mole, purity 92.4%) and aqueous ammonia solution (1100.0 g, 25 %, 16.17 mole) were charged in a Hastelloy reactor (2000 ml) and heated the reaction mixture up to 120°C under agitation and maintained at the same temperature for 5-6 hours. After completion of the reaction, reaction mass was extracted with dichloromethane and followed by evaporation to obtain a crude solid, crystallized the resultant solid in hexane to obtain crystalline product.
Yield: 86 %;
Purity (by GC area %): 96 %
Example 5: Preparation of 2-amino-4-dichlorofluoromethyl pyridine
2-fluoro-4-dichlorofluoromethylpyridine (160.0 g, 0.75mole, purity 92.4%) and aqueous ammonia solution (1150.0 g; 25 %) were charged in a Hastelloy reactor (2000ml) and heated the reaction mixture up to 120°C under agitation and maintained at the same temperature for 5-6 hours. After completion of the reaction, reaction mass was extracted with dichloromethane and followed by evaporation to obtain a crude solid, crystallized the resultant solid in hexane to obtain crystalline product.
Yield: 86 %;
Purity (by GC area %): 96 %.
Example 6: Preparation of 2-amino-6-chloro-4-trifluoromethylpyridine
2,6-dichloro-4-trifluoromethylpyridine (147.5 g) and aqueous ammonia solution (1101 g; 25 %) were charged in a Hastelloy autoclave reactor at 30°C. The reaction mass was gradually heated to a temperature of 150°C and pressure of ~16 bar. 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 extracted with dichloromethane and concentrated to obtain crude product. The crude product was crystallised in hexane. The crystallised product further purified by distillation to obtain pure product.
Yield: 85 %;
Purity (by GC area %): 98 %.
Example 7: Preparation of 3-chloro-N-methyl-5-(trifluoromethyl)-2-pyridinamine
2,3-dichloro-5-(trifluoromethyl) pyridine (37g) and aqueous methyl amine solution (66 g; 40 %) were charged in an autoclave reactor. The reaction mass was heated to 115 °C and pressure observed was 5 bar in the reactor. The pressure was reduced from 5 bar to 3.5 bar during reaction completion. Upon completion, the reactor was cooled to room temperature and dichloromethane (200 g) was added into the reaction mass. The reaction mass was separated into layers and organic layer was evaporated on rota vapour under reduced pressure to isolate product.
Yield: 97.5 %;
Purity (by GC area %): 99 %.

WE CLAIM:

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

Formula 1
wherein X and X1 are independently selected from a halogen, R is independently selected from hydrogen or C1-C3 alkyl; n ranges from 0-3,
comprising the step of reacting a compound of formula 2,

Formula 2
wherein L is a leaving group, X and X1 are independently selected from a halogen, n ranges from 0-3,
with an aqueous solution of (R)2NH, wherein R is independently selected from hydrogen or C1-C3 alkyl; to obtain the compound of formula 1.
2. The process as claimed in claim 1, wherein the (R)2NH is selected from ammonia, methylamine, ethylamine, dimethylamine, diethylamine, propylamine and isopropylamine.
3. The process as claimed in claim 1, wherein the reaction is carried out without using any organic solvent.
4. The process as claimed in claim 1, wherein the solution of (R)2NH has concentration in the range of 20 to 70 % by mass of (R)2NH.
5. The process as claimed in claim 1, wherein the reaction is carried out at a temperature in the range of 25 to 120°C.
6. The process as claimed in claim 1, wherein the reaction is carried out at a temperature in the range of 40 to 80°C.
7. The process as claimed in claim 1, wherein the reaction is carried out in 2-8 hours.
8. The process as claimed in claim 1, wherein the reaction is carried out without using any catalyst.
9. The process as claimed in claim 1, wherein the reaction is carried out without using any phase transfer catalyst.