FIELD OF THE INVENTION
The present invention provides a process for preparation of nicotinamide compounds and the derivatives thereof using completely anhydrous conditions.

BACKGROUND OF INVENTION
Nicotinamides compounds are useful as pesticides. These are also important synthetic building blocks for the preparation of agrochemical active compounds, such as flonicamid, useful as an insecticide.
EP0580374B1 provides a process for preparation of pyridine amides and their salt. In particular, it provides a process for preparation of halogenated nicotinamides from halogenated nicotinic acids using thionyl chloride, followed by treatment with an aqueous ammonia.
JP2009235062A discloses a method of reacting 2-chloro-6-trifluoromethylnicotinic acid with thionyl chloride or oxalyl chloride to produce 2-chloro-6-trifluoromethylnicotinic acid chloride followed by reaction with an aqueous ammonia to produce 2-chloro-6-trifluoromethylnicotinamide.
CN107337665A provides a process for preparation of 6-trifluoromethylnicotinamide by reacting 6-trifluoromethylnicotinonitrile with sulfuric acid in presence of water and glacial acetic acid, followed by reaction with aqueous ammonia.
These processes require longer reaction time and uses aqueous reagent which generate large quantity of aqueous effluent. Also, the yield obtained is not economically satisfactory.
The present invention provides an effluent free and high yielding process for preparation of nicotinamide compounds.

OBJECT OF THE INVENTION
The present invention provides a process for preparation of nicotinamide compounds and derivatives thereof using anhydrous conditions.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of nicotinamide compounds and derivatives thereof, comprising the steps of:
a) reacting nicotinic acid compounds with a chlorinating agent in a solvent to get a reaction mixture 1;
b) recovering the excess of chlorinating agent from the reaction mixture 1 to obtain a reaction mixture 2; and
c) aminating the reaction mixture 2 to obtain the nicotinamide compounds and derivatives thereof.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the nicotinic acid compounds and derivatives thereof includes nicotinic acid, 4-trifluoromethylnicotinic acid, 6-trifluoromethylnicotinic acid, 2-trifluoromethylnicotinic acid, difluoromethylnicotinic acids; 4-chlorodifluoronicotinic acid, 6-chlorodifluoromethylnicotinic acid, 2-chlorodifluoromethylnicotinic acid, 4-dichlorofluoronicotinic acid, 6-dichlorofluoromethylnicotinic acid, 2-dichlorofluoromethylnicotinic acid, 6-chloro-4-trifluoromethylnicotinic acid, 5-chloro-4-trifluoromethylnicotinic acid, 2-chloro-4-trifluoromethylnicotinic acid, 4-chloro-2-trifluoromethylnicotinic acid, 6-chloro-2-trifluoromethylnicotinic acid, 4-chloro-6-trifluoromethylnicotinic acid, 5-chloro-6-trifluoromethylnicotinic acid, 2-chloro-6-trifluoromethylnicotinic acid and 2,6-dichloro-4-trifluoromethylnicotinic acid.
As used herein, the nicotinamide compounds and derivatives prepared by the process of present invention includes nicotinamide, 4-trifluoromethylnicotinamide, 6-trifluoromethylnicotinamide, 2-trifluoromethylnicotinamide, difluoromethylnicotinamide; 4-chlorodifluoronicotinamide, 6-chlorodifluoromethylnicotinamide, 2-chlorodifluoromethylnicotinamide, 4-dichlorofluoronicotinamide, 6-dichlorofluoromethylnicotinamide, 2-dichlorofluoromethylnicotinamide, 6-chloro-4-trifluoromethylnicotinamide, 5-chloro-4-trifluoromethylnicotinamide, 2-chloro-4-trifluoromethylnicotinamide, 4-chloro-2-trifluoromethylnicotinamide, 6-chloro-2-trifluoromethylnicotinamide, 4-chloro-6-trifluoromethylnicotinamide, 5-chloro-6-trifluoromethylnicotinamide, 2-chloro-6-trifluoromethylnicotinamide and 2,6-dichloro-4-trifluoromethylnicotinamide.
In an embodiment of the present invention, the step of reacting nicotinic acid compounds with a chlorinating agent is carried out in a first organic solvent selected from a group consisting of non-polar organic solvent, ethers, or alkyl acetate.
The ‘non-polar organic solvent’ is selected from a group consisting of toluene, benzene, chlorobenzene, chloroform, dichloromethane, hexane, and xylene.
In another embodiment of the present invention, the chlorinating agent may be selected from a group consisting of thionyl chloride, oxalyl chloride, phosgene and phosphoryl chloride or the like. The molar ratio of chlorinating agent is in the range of 2 to 5 mole equivalents. The preferred chlorinating agent for present invention is thionyl chloride.
The excess quantity of chlorinating agent used in present invention is recovered and recycled for further batches.
In another embodiment, the step of reacting nicotinic acid compounds with a chlorinating agent is carried out in a presence of catalytic amount of dimethyl formamide. The catalytic amount of dimethyl formamide refers to molar ratio selected in the range 0.01-0.05 of dimethylformamide to the nicotinic acid compound.
In another embodiment, the excess thionyl chloride is recovered from reaction mixture as mixture of thionyl chloride and a first non-polar organic solvent. This mixture may be used for further batches.
The step of reacting nicotinic acid compound with a chlorinating agent involves formation of an acyl intermediate, which is preferably not isolated.
In another embodiment of the present invention, the step of amination is carried out in a second non-polar organic solvent is selected from a group consisting of ethyl acetate, toluene, chlorobenzene, chloroform, hexane and xylene or the like.
The solvent used for present invention may be dehydrated to remove moisture to attain moisture content of less than 500ppm. In a preferred embodiment, solvent have moisture in the range of less than 500ppm.
In another embodiment, chlorination is performed in toluene or xylene and amination is carried out in ethyl acetate as solvent.
In an embodiment of the present invention, chlorination is carried out at a temperature in the range from 25-30°C for 3 hours.
In an embodiment, chlorination and amination are carried out in a single solvent selected from a group consisting of toluene, benzene, chlorobenzene, chloroform, hexane, xylene, ethylacetate or the like.
The aminating agent used for the present invention is selected from primary amine such as ammonia, methylamine, ethylamine, propyl amine and secondary amine selected from dimethyl amine and diethyl amine or the like. The aminating agent are used in gaseous and in organic form, however aqueous form of amine reagent is avoided to eliminate aqueous effluent.
The aminating agent used in the present invention is anhydrous or contains less than 500ppm or preferably less than 300ppm of moisture.
The molar ratio of aminating agent may be selected from 1 to 8 mole equivalents to the nicotinic acid compound.
In amination process, addition of aminating agent is carried out at 0-5°C followed by heating the reaction mixture at a temperature of 50-90°C for 1 hour.
In another important embodiment, the reaction mixture 2 is filtered at a temperature range of 40-70°C. Preferably, reaction mixture is filtered at temperature 50°C.
The crude product is washed with a solvent selected from a group consisting of diethylether, ethylacetate, toluene, dichloromethane and chloroform or the like and dried to isolate nicotinamide compounds and derivatives thereof.
In a specific embodiment, the present invention provides a process for preparation of nicotinamide compounds and derivative thereof, comprising the steps of:
a) reacting nicotinic acid compounds with a chlorinating agent in a solvent to get a reaction mixture 1;
b) recovering the excess of chlorinating agent from the reaction mixture of step a) to obtain a reaction mixture 2;
c) aminating the reaction mixture 2 to obtain a reaction mixture 3;
d) filtering the reaction mixture 3 at a temperature of 40 to 70°C; and
e) isolating nicotinamide compound and the derivatives thereof from the filtrate of step d).
In a specific embodiment, the present invention provides a process for preparation of nicotinamide, comprising the steps of:
a) reacting nicotinic acid with a thionyl chloride in a solvent to get a reaction mixture 1;
b) recovering the excess of thionyl chloride from the reaction mixture of step a) to obtain a reaction mixture 2;
c) reacting the reaction mixture 2 with anhydrous gaseous ammonia to obtain a reaction mixture 3;
d) filtering the reaction mixture 3 at a temperature of 40 to 70°C; and
e) isolating nicotinamide from the filtrate of step d).
In another specific embodiment, the present invention provides a process for preparation of 6-trifluoromethylnicotinamide, comprising the steps of:
a) reacting 6-trifluoromethylnicotinic acid with thionyl chloride optionally in presence of a catalytic amount of dimethyl formamide to obtain a reaction mixture 1;
b) recovering excess of thionyl chloride from the reaction mixture 1 to obtain a reaction mixture 2;
c) reacting the reaction mixture 2 with an anhydrous gaseous ammonia to obtain a reaction mixture 3;
d) filtering the reaction mixture 3 at a temperature of 40 to 70°C; and
e) isolating 6-trifluoromethylnicotinamide from the filtrate of step d).
In another specific embodiment, the present invention provides a process for preparation of 4-trifluoromethylnicotinamide, comprising steps of:
a) reacting 4-trifluoromethylnicotinic acid with thionyl chloride optionally in presence of a catalytic amount of dimethyl formamide to obtain a reaction mixture 1;
b) recovering thionyl chloride from the reaction mixture 1 to obtain a reaction mixture 2;
c) reacting the reaction mixture 2 with anhydrous gaseous ammonia to obtain a reaction mixture 3;
d) filtering the reaction mixture 3 at a temperature of 40 to 70°C; and
e) isolating 4-trifluoromethylnicotinamide from the filtrate of step d).
In another specific embodiment, the present invention provides a process for preparation of 4-trifluoromethyl-N,N-dimethylnicotinamide, comprising steps of:
a) reacting 4-trifluoromethylnicotinic acid with thionyl chloride optionally in presence of catalytic amount of dimethyl formamide to obtain a reaction mixture 1;
b) recovering excess of thionyl chloride from the reaction mixture 1 to obtain a reaction mixture 2;
c) reacting reaction mixture 2 with anhydrous gaseous ammonia to obtain a reaction mixture 3;
d) filtering the reaction mixture 3 at a temperature of 40 to 70°C; and
e) isolating 4-trifluoromethyl-N,N-dimethylnicotinamide from the filtrate of step d).
In another specific embodiment, the present invention provides a process for preparation of 6-chloro-4-trifluoromethylnicotinamide, comprising steps of:
a) reacting 6-chloro-4-trifluoromethylnicotinic acid with thionyl chloride optionally in presence of catalytic amount of dimethyl formamide to obtain a reaction mixture 1;
b) recovering excess of thionyl chloride from the reaction mixture 1 to obtain a reaction mixture 2;
c) reacting the reaction mixture 2 with anhydrous gaseous ammonia to obtain reaction mixture 3;
d) filtering the reaction mixture 3 at a temperature of 40 to 70°C; and
e) isolating 6-chloro-4-trifluoromethylnicotinamide from the filtrate of step d).
In another embodiment of the present invention, the step of recovering thionyl chloride may additionally involve recovering the first non-polar organic solvent.
In another embodiment of the present invention, the step of amination may involve addition of the second non-polar organic solvent prior to the reaction with aminating agent.
The nicotinic acid compound may be contaminated with impurities. The impurities are trifluoromethyl isomers of nicotinic acid compounds used as reactant, in quantity less than 0.5% and more preferably less than 0.1%.
In an embodiment, the 4-trifluoromethyl nicotinic acid contains 6-trifluoromethyl nicotinic acid in the quantity less than 0.5%.
In an embodiment, nicotinamide compounds may contain impurity in the quantity less than 1% and preferably less than 0.5%.
In an embodiment, 4-trifluoromethylnicotinic acid taken as reactant contains 6-trifluoromethylnicotinic acid in the quantity less than 0.5%.
In an embodiment, 4-trifluoromethylnicotinamide prepared from 4-trifluoromethylnicotinic acid having less than 1% of 6-trifluoromethylnicotinic acid contamination, is containing impurities less than 0.5%. The impurities are 4-trifluoromethyl-N,N-dimethylnicotinamide, 6-trifluoromethyl-N,N-dimethylnicotinamide and 6-trifluoromethylnicotinamide.
The yield obtained in the present process for the nicotinamide compounds is greater than 75% and preferably greater than 85%.
The purity of nicotinamide compounds is greater than 99% and analysis is carried out on HPLC.
The present invention is a batch process and may be carried out in continuous flow mode also. Hence, the present invention is not limited to batch only.
The present invention eliminates the formation of aqueous effluents and involve complete recycle and reuse of the organic effluents, therefore it is an environment friendly, alternative to the known processes for commercial production of nicotinamide. Hence, present invention provides an effluent free process for preparation of halogenated nicotinamides.
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 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 4-trifluoromethylnicotinamide
Toluene (440g, 4744 mmol, 15.6 eq. mol), 4-(trifluoromethyl) nicotinic acid (60g, 305 mmol, 1 mol. eq.) and N, N-dimethylformamide (0.23g, 3.05 mmol, 0.01 eq. mol) were added to a reactor at 25-300C. Thionyl chloride (110g, 915 mmol, 3.0 eq. mol) was added dropwise in the reactor. The reaction mass was heated for 3 hours under reflux. After completion of the reaction, the reaction mixture was subjected to distillation to remove excess of thionyl chloride and toluene under vacuum to obtain crude mixture. The mixture was diluted with ethyl acetate (400g, 4495 mmol, 14.75 eq. mol) and reacted with gaseous ammonia (36g, 2114 mmol, 6.7 eq. mol) at 0-5°C, followed by heating at 70°C for one hour. The crude mass was filtered in hot condition and filtrate was distilled to remove ethyl acetate and toluene. The concentrated crude mass (50g) was diluted with ethyl acetate (75g, 843 mmol, 2.76 eq. mol) and then filtered at 0-50C to obtain product (52g). The product was further dried under vacuum at 60°C for 2 hours to obtain 4-trifluoromethylnicotinamide (45g).
Purity (HPLC): 99.5%
Yield: 77%
Example 2. Preparation of 6-chloro-4-trifluoromethylnicotinamide
Toluene (575g, 6240 mmol, 15.6 eq. mol), 6-chloro-4-(trifluoromethyl) nicotinic acid (90.2g, 400 mmol, 1 eq. mol) and N, N-dimethylformamide (0.3g, 4 mmol, 0.01 eq. mol) were added to a reactor at 25-300C. Thionyl chloride (143g, 1200 mmol, 3.0 eq. mol) was added dropwise in the reaction flask. The reaction mass was heated for 3 hours under reflux. After completion of the reaction, the reaction mixture was subjected to distillation to remove excess of thionyl chloride and toluene under vacuum to obtain crude mixture. The crude mixture was diluted with ethyl acetate (519.9g, 5900 mmol, 14.75 eq. mol) and reacted with gaseous ammonia (45.6g, 2680 mmol, 6.7 eq. mol) at 0-50C, followed by heating at 70°C for one hour. The crude mass was filtered in hot condition and filtrate was distilled to remove ethyl acetate and toluene. The concentrated crude mass (75g) was diluted with ethyl acetate (97.27g, 1104 mmol, 2.76 eq. mol) and then filtered at 0-5°C to obtain product (72g). The product was further dried under vacuum at 60°C for 2 hours to obtain titled compound (70g).
Purity (HPLC): 99.5%
Yield: 78%
Example 3. Preparation of 6-chloro-2-trifluoromethylnicotinamide
Toluene (575g, 6240 mmol, 15.6 eq. mol), 6-chloro-2-(trifluoromethyl) nicotinic acid (90.2g, 400 mmol, 1 mol. eq.) and N,N-dimethylformamide (0.3g, 4 mmol, 0.01 eq. mol) were added to a reactor at 25-30°C. Thionyl chloride (143g, 1200mmol, 3.0 eq. mol) was added dropwise in the reaction flask. The reaction mass was heated for 3 hours under reflux. After completion of the reaction (check point 6-chloro-2-TFMNA < 1%), the reaction mixture was subjected to distillation to remove excess of thionyl chloride and toluene under vacuum to obtain crude mixture. The crude mixture was diluted with ethyl acetate (519.9g, 5900 mmol, 14.75 eq. mol) and reacted with gaseous ammonia (45.6g, 2680 mmol, 6.7 eq. mol) at 0-5°C, followed by heating at 70°C for one hour.
The crude mass was filtered in hot condition and filtrate was distilled to remove ethyl acetate and toluene. The concentrated crude mass (77g) was diluted with ethyl acetate (97.27g, 1104 mmol, 2.76 eq. mol) and then filtered at 0-5°C to obtain product (73g). The product was further dried under vacuum at 60°C for 2 hours to obtain titled compound.
Purity (HPLC): 99.6%
Yield: 77%

CLAIMS:

WE CLAIM:
1. A process for preparation of nicotinamide derivatives, comprising the steps of:
a) reacting nicotinic acid compounds with a chlorinating agent in a solvent to get a reaction mixture 1;
b) recovering the excess of chlorinating agent from the reaction mixture 1 to obtain a reaction mixture 2; and
c) aminating the reaction mixture 2 to obtain the nicotinamide compounds.
2. The process as claimed in claim 1, wherein the chlorination reaction of step a) is carried out in a first organic solvent selected from a group consisting of non-polar organic solvent, ethers and alkyl acetates.
3. The process as claimed in claim 2, wherein the non-polar organic solvent is selected from a group consisting of toluene, benzene, chlorobenzene, chloroform, dichloromethane, hexane, and xylene or a mixture thereof.
4. The process as claimed in claim 1, wherein the chlorinating agent used in step a) is selected from a group consisting of thionyl chloride, oxalyl chloride, phosgene and phosphoryl chloride.
5. The process as claimed in claim 1, wherein the chlorination reaction of step a) is carried out in presence of catalytic amount of dimethyl formamide.
6. The process as claimed in claim 1, wherein the amination reaction of step c) is carried out in a second non-polar organic solvent selected from a group consisting of ethyl acetate, toluene, chlorobenzene, chloroform, hexane and xylene or a mixture thereof.
7. The process as claimed in claim 1, wherein the aminating agent used in step c) is a primary amine selected from ammonia, methylamine, ethylamine, propyl amine and secondary amine selected from dimethyl amine and diethyl amine.
8. The process as claimed in claim 7, wherein the aminating agent used is anhydrous or contains less than 500ppm of moisture.
9. The process as claimed in claim 1, wherein the chlorination reaction of step a) is carried out at a temperature in the range from 25-30°C.
10. The process as claimed in claim 1, wherein the amination reaction of step c) is carried out at a temperature in the range from 50-90°C.