Description:FIELD
The present disclosure relates to a fungicide and a process for its preparation.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Mandipropamid is a mandelamide fungicide used for the control of oomycete fungal pathogens in crops such as grapes, potatoes, tomatoes, cucurbits and the like. Mandipropamid is highly active against spore germination, inhibits mycelia growth during the incubation period and its uptake into the leaf tissue assures good translaminar activity. It acts as a cellulose synthesis inhibitor.
Mandipropamid is chemically known as 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide and is structurally represented as formula (I) below:

Formula (I)
The conventional methods for the preparation of Mandipropamid are associated with drawbacks such as heating of nitromethane under highly basic conditions which is extremely unsafe from a commercial perspective. Further, the conventional processes involve the use of expensive and harmful reagents which is not safe and not cost effective. Further, the yield and purity of Mandipropamid obtained by conventional processes is comparatively low.
Therefore, there is felt a need to provide a process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) that mitigates the aforestated drawbacks or at least provides an alternative solution.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide.
Yet another object of the present disclosure is to provide a process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide with a comparatively better purity and yield.
Yet another object of the present disclosure is to provide a process for the preparation of 2-methoxy-4-((E)-2-nitrovinyl)phenol at lower temperature.
Still another object of the present disclosure is to provide a process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide with less energy consumption.
Yet another object of the present disclosure is to provide a process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide with lesser safety hazards.
Still another object of the present disclosure is to provide a simple and cost-effective process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide.
Yet another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide.

Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for the preparation of 2-(4-chloro-phenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid). The process comprises reacting vanillin and nitromethane by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol. The 2-methoxy-4-((E)-2-nitrovinyl)phenol is reduced by using a reducing agent in a second fluid medium in an inert atmosphere at a second predetermined temperature for a second predetermined time period under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol. The 4-(2-aminoethyl)-2-methoxyphenol is coupled with 4-chloro-a-hydroxy benzene acetic acid in the presence of a catalyst in a third fluid medium at a third predetermined temperature for a third predetermined time period under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide. The N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide is reacted with propargyl bromide by using a second base in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The first base is selected from the group consisting of ammonium acetate and sodium acetate.
The first fluid medium is acetic acid.
The first predetermined temperature is in the range of 40 °C to 75 °C.
The first predetermined time period is in the range of 4 hours to 8 hours.
The second fluid medium is selected from the group consisting of methanol, isopropanol and t-butanol.
The inert atmosphere is selected from nitrogen and argon.
The second predetermined temperature is in the range of 30 °C to 70 °C.
The second predetermined time period is in the range of 5 hours to 10 hours.
The catalyst is selected from boric acid, phosphorus trichloride and phosphorous pentoxide.
The third fluid medium is selected from the group consisting of dimethylformamide and 1,4 dioxane.
The third predetermined temperature is in the range of 90 °C to 125 °C.
The third predetermined time period is in the range of 5 hours to 10 hours.
The second base is selected from the group of bases consisting of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.
The fourth fluid medium is selected from the group consisting of ethylene dichloride, methylene dichloride and ethyl acetate.
The fourth predetermined temperature is in the range of 50 °C to 75 °C.
The fourth predetermined time period is in the range of 2 hours to 6 hours.
The mass ratio of vanillin to nitromethane is 1:0.61.
The mass ratio of 4-(2-aminoethyl)-2-methoxyphenol to 4-chloro-a-hydroxy benzene acetic acid is 1:0.95.
The mass ratio of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide to propargyl bromide is 1:0.96.
The process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) comprises the steps of reacting vanillin and nitromethane by using ammonium acetate in acetic acid at 55 °C for 5.5 hours under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol. The 2-methoxy-4-((E)-2-nitrovinyl)phenol is reduced by using H2/Pd-C in methanol in nitrogen atmosphere at 50 °C for 7.5 hours under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol. The 4-(2-aminoethyl)-2-methoxyphenol is coupled with 4-chloro-a-hydroxy benzene acetic acid in the presence of boric acid in dimethyl formamide at 105 °C for 7.5 hours under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide. The N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide is reacted with propargyl bromide by using sodium hydroxide in ethylene dichloride at 65 °C for 4 hours under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid), further comprising cooling the product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) to a temperature in the range of 20 °C to 30 °C followed by adding water to obtain a biphasic mixture comprising an organic layer and an aqueous layer. The organic layer is separated and concentrated to obtain solids. The solids are recrystallized by using a solvent followed by filtration and dried at a temperature in the range of 40 °C to 60 °C to obtain 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The solvent is an alcohol selected from the group consisting of methanol, isopropanol and t-butanol.
The yield of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is in the range of 70 % to 75 %.
The purity of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is in the range of 97 % to 99 % by HPLC.
DETAILED DESCRIPTION
The present disclosure relates to a process for the preparation of a fungicide. Particularly, the present disclosure relates to a process for the preparation of 2-(4-chloro-phenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
Embodiments, of the present disclosure, will now be described herein. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer, or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
The conventional methods for the preparation of Mandipropamid are associated with drawbacks such as heating of nitromethane under highly basic conditions which is extremely unsafe from a commercial perspective. Further, the conventional processes involve the use of expensive and harmful reagents which is not safe and not cost effective. Further, the yield and purity of Mandipropamid obtained by conventional processes is comparatively low.
The present disclosure provides an improved process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The process of the present disclosure is simple, environment friendly, economical and results in improved yield and purity of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
In an embodiment of the present disclosure, the process for the preparation of 2-(4-chloro-phenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy) acetamide (Mandipropamid) comprises the following steps:
i. reacting vanillin and nitromethane by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol;
ii. reducing 2-methoxy-4-((E)-2-nitrovinyl)phenol by using a reducing agent in a second fluid medium in an inert atmosphere at a second predetermined temperature for a second predetermined time period under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol;
iii. coupling 4-(2-aminoethyl)-2-methoxyphenol with 4-chloro-a-hydroxybenzene acetic acid in the presence of a catalyst in a third fluid medium at a third predetermined temperature for a third predetermined time period under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide; and
iv. reacting N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and propargyl bromide by using a second base in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).

The overall scheme for the preparation of Mandipropamid is represented as Scheme-I below:

Scheme-I

The process is described in detail below:
Step I: Preparation of 2-methoxy-4-((E)-2-nitrovinyl)phenol by using Vanillin
In a first step, vanillin is reacted with nitromethane by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol.
In this step, a predetermined amount of vanillin and a predetermined amount of a first fluid medium are mixed at a temperature in the range of 25 °C to 40 °C under stirring to obtain a first mixture. A predetermined amount of nitromethane and a predetermined amount of a first base are added to the first mixture and heated to a first predetermined temperature for a first predetermined time period under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol.
The first reaction mixture is cooled to a temperature in the range of 25 °C to 40 °C to obtain a cooled first reaction mixture. The cooled first reaction mixture is filtered to obtain solids comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol and a first filtrate. The solids are washed with water followed by washing with a solution of 1:1 methanol: water to obtain a wet mass of 2-methoxy-4-((E)-2-nitrovinyl)phenol. The wet mass of 2-methoxy-4-((E)-2-nitrovinyl)phenol is dried at a temperature in the range of 40 °C to 55 °C to obtain 2-methoxy-4-((E)-2-nitrovinyl)phenol.
In an embodiment of the present disclosure, the mass ratio of vanillin to nitromethane is 1:0.61.
In an embodiment of the present disclosure, the first base is selected from the group consisting of ammonium acetate and sodium acetate. In an exemplary embodiment of the present disclosure, the first base is ammonium acetate.
In an embodiment of the present disclosure, the first fluid medium is acetic acid.
In an embodiment of the present disclosure, the first predetermined temperature is in the range of 40 °C to 75 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 55 °C.
In accordance with the present disclosure, the reaction of vanillin and nitromethane by using ammonium acetate as a base and acetic acid as a solvent is carried out at low temperature which results in enhanced yield as well as enhanced purity of 2-methoxy-4-((E)-2-nitrovinyl)phenol.
In accordance with the present disclosure, the reaction of vanillin and nitromethane is carried out at a lower temperature i.e. 50 °C to 55 °C as compared to conventional processes wherein the reaction is carried out at higher temperatures, thereby reducing consumption of energy as well as making the process economical and environment friendly.
Further, the advantages of carrying out the reaction of vanillin and nitromethane at low temperatures are as follows:
Reduced Risk of Hazardous Conditions: The risk of hazardous conditions is reduced by carrying out the reaction at lower temperatures thereby minimizing the risk of thermal runaway reactions, explosions or other safety hazards associated with high-temperature operations. This is important for reactions involving flammable reactants like nitromethane.
Decreased Equipment Stress: Equipment used for high-temperature reactions often experience greater wear and tear. Operating at lower temperatures can prolong the life of reaction vessels, reducing maintenance and replacement costs.
Better Control of Exothermic Reactions: At lower temperatures, exothermic reactions are more easily controlled, decreasing the likelihood of accidental overheating and associated dangers.
Minimized Decomposition: Sensitive reactants or products that may decompose at high temperatures are preserved, thus maintaining yield and purity.
Reduced Energy Consumption and lower operational costs: Reduced energy needs and simpler heating equipment contributes to lower operational costs, making the process more economically viable. This contributes to overall cost savings in industrial processes, especially when scaled up.
Reduced Carbon Footprint: By consuming less energy, low-temperature reactions contribute to a smaller carbon footprint, aligning with green chemistry principles and sustainability goals.
Fewer Emissions: Lower temperature reactions can reduce the emission of volatile organic compounds (VOCs) and other pollutants, contributing to a cleaner and safer working environment.
Easier Scale-Up: Processes conducted at moderate temperatures are generally easier to scale up from laboratory to industrial levels. The reduced thermal stress on equipment makes large-scale production more feasible and less risky.
Consistent Quality across Scales: Achieving consistent quality and yield across different production scales is often more manageable with low-temperature reactions due to their stability and control.
In an embodiment of the present disclosure, the first predetermined time period is in the range of 4 hours to 8 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 5.5 hours.
In an exemplary embodiment, a schematic representation for the preparation of 2-methoxy-4-((E)-2-nitrovinyl)phenol is given as scheme A below:

SCHEME A
STEP II: Preparation of 4-(2-aminoethyl)-2-methoxyphenol
In a second step, 2-methoxy-4-((E)-2-nitrovinyl)phenol is reduced by using a reducing agent in a second fluid medium in an inert atmosphere at a second predetermined temperature for a second predetermined time period under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol.
In this step, a predetermined amount of 2-methoxy-4-((E)-2-nitrovinyl)phenol and a predetermined amount of a second fluid medium are mixed in an inert atmosphere to obtain a second mixture. A predetermined amount of reducing agent is added to the second mixture and heated to a second predetermined temperature for a second predetermined time period under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol.
The second reaction mixture is filtered to obtain solids comprising 4-(2-aminoethyl)-2-methoxyphenol and a second filtrate. The solids are washed with methanol to obtain a wet mass of 4-(2-aminoethyl)-2-methoxyphenol and a third filtrate.
The third filtrate is concentrated under reduced pressure at a temperature in the range of 40 °C to 55 °C followed by cooling to a temperature in the range of 5 °C to 20 °C to obtain slurry. The slurry is filtered to obtain solids followed by washing the solids with methanol to obtain a wet mass of 4-(2-aminoethyl)-2-methoxyphenol. The wet mass is dried at a temperature in the range of 40 °C to 60 °C to obtain 4-(2-aminoethyl)-2-methoxyphenol.
In an embodiment of the present disclosure, the reducing agent is selected from the group consisting of H2-Pd/C and H2-Raney nickel. In an exemplary embodiment of the present disclosure, the reducing agent is H2-Pd/C.
In an embodiment of the present disclosure, Palladium on carbon (Pd/C) is a 50% wet powder with water.
In an embodiment of the present disclosure, the second fluid medium is selected from the group consisting of methanol, isopropanol and t-butanol. In an exemplary embodiment of the present disclosure, the second fluid medium is methanol.
In an embodiment of the present disclosure, the inert atmosphere is selected from nitrogen and argon. In an exemplary embodiment of the present disclosure, the inert atmosphere is nitrogen.
In an embodiment of the present disclosure, the second predetermined temperature is in the range of 30 °C to 70 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 50 °C.
In an embodiment of the present disclosure, the second predetermined time period is in the range of 5 hours to 10 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 7.5 hours.
In an exemplary embodiment, a schematic representation for the preparation of 4-(2-aminoethyl)-2-methoxyphenol is given as scheme B below:

Scheme B
STEP III: Preparation of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide
In a third step, 4-(2-aminoethyl)-2-methoxyphenol is coupled with 4-chloro-a-hydroxy benzene acetic acid in the presence of a catalyst in a third fluid medium at a third predetermined temperature for a third predetermined time period under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide.
In this step, a predetermined amount of 4-(2-aminoethyl)-2-methoxy phenol, a predetermined amount of 4-chloro-a-hydroxy benzene acetic acid and a predetermined amount of a third fluid medium are mixed at a temperature in the range of 25 °C to 40 °C to obtain a third mixture. A predetermined amount of a catalyst is added to the third mixture followed by heating to a third predetermined temperature for a third predetermined time period under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide.
The third reaction mixture is cooled to a temperature in the range of 25 °C to 40 °C to obtain a cooled third reaction mixture. Water is added to the cooled third reaction mixture followed by extracting with dichloromethane to obtain a biphasic mixture comprising an organic layer (dichloromethane layer) and an aqueous layer. In an embodiment the ratio of 4-(2-aminoethyl)-2-methoxy-phenol to water is in the range of 1:2 to 1:6. The organic layer is separated from the biphasic layer followed by washing with water and is distilled under reduced pressure to obtain a crude N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide.
Isopropyl alcohol (IPA) is added to the crude N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide followed by heating to a temperature in the range of 50 °C to 60 °C for a time period in the range of 30 minutes to 45 minutes under stirring and then cooled to a temperature in the range of 25 °C to 40 °C followed by filtration, washing with isopropyl alcohol and drying at a temperature in the range of 40 °C to 60 °C to obtain N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide.
In an embodiment of the present disclosure, the mass ratio of 4-(2-aminoethyl)-2-methoxyphenol to 4-chloro-a-hydroxy benzene acetic acid is 1: 0.96.
In an embodiment of the present disclosure, the catalyst is selected from the group consisting of boric acid, phosphorus trichloride and phosphorus pentoxide. In an exemplary embodiment of the present disclosure, the catalyst is boric acid.
The conventional methods for the preparation of carboxamides from carboxylic acids and amines require conversion of carboxylic acid to acid halides, anhydrides or use of activating agents such as dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBt), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and the like. These conventional methods suffer from several disadvantages such as environmental unfriendliness, poor selectivity, poor step economy, formation of by-products and unsuitability for large-scale preparation.
In accordance with the present disclosure, the use of boric acid as a catalyst for the preparation of carboxamides from carboxylic acids and amines is environment friendly, economical, and industrially viable. Further, boric acid is easily available. Furthermore, the product N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide is obtained with high yield using only 3% of boric acid.
In an embodiment of the present disclosure, the third fluid medium is selected from the group consisting of dimethylformamide and 1,4-dioxane. In an exemplary embodiment of the present disclosure, the third fluid medium is dimethylformamide.
In an embodiment of the present disclosure, the third predetermined temperature is in the range of 90 °C to 125 °C. In an exemplary embodiment of the present disclosure, the third predetermined temperature is 105 °C.
In an embodiment of the present disclosure, the third predetermined time period is in the range of 5 hours to 10 hours. In an exemplary embodiment of the present disclosure, the third predetermined time period is 7.5 hours.
In an exemplary embodiment, a schematic representation for the preparation N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide is given as scheme C below,

Scheme C
STEP IV: Preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid)
In a fourth step, N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide is reacted with propargyl bromide by using a second base in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy) acetamide (Mandipropamid).
In this step, a predetermined amount of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and a predetermined amount of a fourth fluid medium are mixed at a temperature in the range of 20 °C to 25 °C to obtain a fourth mixture. The fourth mixture is heated to a temperature in the range of 30 °C to 40 °C followed by adding a predetermined amount of a second base in a dropwise manner over a time period in the range of 25 minutes to 35 minutes under stirring and maintained for a time period in the range of 1 hour to 5 hours to obtain a fourth mixture. A predetermined amount of propargyl bromide (80% solution in Toluene) is added to the fourth mixture over a time period in the range of 20 minutes to 35 minutes followed by heating at a fourth predetermined temperature for a fourth predetermined time period under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The process for the preparation of Mandipropamid, further comprises cooling the product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) to a temperature in the range of 20 °C to 30 °C followed by adding water to obtain a biphasic mixture comprising an organic layer and an aqueous layer. The organic layer is separated and concentrated to obtain solids. The solids are recrystallized using a solvent followed by filtration and dried at a temperature in the range of 40 °C to 60 °C to obtain 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The solvent is an alcohol selected from the group consisting of methanol, isopropanol and t-butanol.
Particularly, the product mixture is cooled to a temperature in the range of 25 °C to 30 °C followed by adding water and stirring for a time period in the range of 10 minutes to 25 minutes to obtain a first biphasic mixture comprising a first organic layer and an aqueous layer. The first organic layer is separated from the biphasic mixture and washed with water to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer is separated from the second biphasic mixture. The first organic layer and second organic layer were combined and concentrated under reduced pressure to obtain a crude product comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid). The crude product is recrystallized (triturated) with isopropyl alcohol followed by filtration and drying at a temperature in the range of 40 °C to 60 °C to obtain 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy) acetamide (Mandipropamid).
In an embodiment of the present disclosure, the second base is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. In an exemplary embodiment of the present disclosure, the second base is sodium hydroxide.
In an embodiment of the present disclosure, the fourth fluid medium is selected from the group consisting of ethylene dichloride, methylene dichloride and ethyl acetate. In an exemplary embodiment of the present disclosure, the fourth fluid medium is ethylene dichloride.
In an embodiment of the present disclosure, the fourth predetermined temperature is in the range of 50 °C to 75 °C. In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 65 °C.
In an embodiment of the present disclosure, the fourth predetermined time period is in the range of 2 hours to 6 hours. In an exemplary embodiment of the present disclosure, the fourth predetermined time period is 4 hours.
In an embodiment of the present disclosure, the mass ratio of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide to propargyl bromide is 1: 0.96.
In accordance with the present disclosure, the temperature and time period conditions are optimized to obtain improved yield and purity of Mandipropamid.
In an embodiment of the present disclosure, the yield of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is in the range of 70 % to 75 %. In an exemplary embodiment of the present disclosure, the yield of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is 73 %.
In an embodiment of the present disclosure, the purity of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is in the range of 97 % to 99 %. In an exemplary embodiment of the present disclosure, the purity of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is 98 %.
In an exemplary embodiment, a schematic representation for the preparation 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is given as scheme D below:

Scheme D
In an embodiment of the present disclosure, the process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) comprises the following steps:
i. reacting vanillin and nitromethane by using ammonium acetate in acetic acid at 55 °C for 5.5 hours under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol;
ii. reducing 2-methoxy-4-((E)-2-nitrovinyl)phenol by using H2/Pd-C in methanol in nitrogen atmosphere at 50 °C for 7.5 hours under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol;
iii. coupling 4-(2-aminoethyl)-2-methoxyphenol with 4-chloro-a-hydroxy benzene acetic acid in the presence of boric acid in dimethyl formamide at 105 °C for 7.5 hours under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide; and
iv. reacting N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and propargyl bromide by using sodium hydroxide in ethylene dichloride at 65 °C for 4 hours under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The present disclosure provides a simple, economic, efficient and commercially scalable process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) with a comparatively high purity and high yield.
Further, the present disclosure provides a process for the preparation of Mandipropamid which is carried out at lower temperatures, thereby minimizing the risk of thermal runaway reactions, explosions or other safety hazards associated with high-temperature operations, and making the process simple, economic and easier for scale-up.
The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments are scalable to industrial/commercial process.
EXPERIMENTAL DETAILS
EXAMPLE 1: A process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
Step I: Preparation of 2-methoxy-4-((E)-2-nitrovinyl)phenol
In 2 litre, four necked round bottom flask (RBF) equipped with a condenser thermometer pocket and an agitator, 100 g of vanillin and 100 mL of acetic acid were charged at 30 °C under stirring to obtain a first mixture. 61 g of nitromethane and 99 g of ammonium acetate were added to the first mixture to obtain a first reaction mass. The first reaction mass was heated to 50 °C to 55 °C for 5 hours 30 minutes under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol. The progress of the reaction was monitored by GC and TLC.
Work-up:
After completion of the reaction, the first reaction mixture was cooled to 30 °C to obtain a cooled first reaction mixture. The cooled first reaction mixture was filtered through a Buchner funnel to obtain solids comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol and a first filtrate. The so obtained solid was washed with water followed by washing with a solution of 1:1 of methanol: water to obtain a wet mass of 2-methoxy-4-((E)-2-nitrovinyl)phenol. The wet mass was dried in vacuum tray dryer (VTD) at 50 °C to obtain 2-methoxy-4-((E)-2-nitrovinyl)phenol.
The yield of 2-methoxy-4-((E)-2-nitrovinyl)phenol was 93 % and purity of 2-methoxy-4-((E)-2-nitrovinyl)phenol was 98 %.
Step II: Preparation of 4-(2-aminoethyl)-2-methoxyphenol
In one litre autoclave, 50 g of 2-methoxy-4-((E)-2-nitrovinyl)phenol and 300 mL (6 vol) of methanol were charged under nitrogen atmosphere to obtain a second mixture. To the second mixture 0.05g (0.1%) of 5% Pd/C was added to obtain a second reaction mass. The second reaction mass was hydrogenated using 25 kg of hydrogen gas (H2) under stirring at 50 °C for 7.5 hours to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol. The progress of the reaction was monitored by HPLC and TLC.
Work-up:
After completion of the reaction, the second reaction mixture was cooled and then filtered through Buchner funnel to obtain solids comprising 4-(2-aminoethyl)-2-methoxyphenol and a second filtrate. The solids were washed with 100 ml (2 vol) of methanol to obtain a wet solid of 4-(2-aminoethyl)-2-methoxyphenol and a third filtrate.
The third filtrate was concentrated under reduced pressure at 50 °C up to 2 vol followed by cooling to 10 °C to obtain slurry. The slurry was filtered to obtain a solid comprising 4-(2-aminoethyl)-2-methoxyphenol followed by washing with 50 ml (1 vol) of methanol to obtain a wet solid of 4-(2-aminoethyl)-2-methoxyphenol.
The so obtained wet solids were combined and dried in a vacuum tray dryer (VTD) at 50 °C for 4.5 hours to obtain 4-(2-aminoethyl)-2-methoxyphenol.
The yield of 4-(2-aminoethyl)-2-methoxyphenol was 70 % and the purity of 4-(2-aminoethyl)-2-methoxyphenol was at least 98.5 Area% by HPLC.
Step III: Preparation of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide
In a two litre, four necked round bottom flask equipped with a condenser, thermometer pocket, a dropping funnel, and an agitator, 200 g of 4-(2-aminoethyl)-2-methoxy-phenol, 190 g of 4-chloro-a-hydroxy benzene acetic acid and 200 ml dimethylformamide were charged under stirring to obtain a third mixture. To the third mixture 5.7 g of 3 % of boric acid was added at 30 °C followed by heating to 105 °C under stirring and maintaining the heating for 7.5 hours to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide. The progress of the reaction was monitored by HPLC and TLC.
Work-up:
After completion of the reaction, the third reaction mixture was cooled to 35 °C to obtain a cooled third reaction mixture. 1000 ml (4 vol) of water was added to the cooled third reaction mixture followed by extracting with 1000 ml (4 vol) of dichloromethane to obtain a first organic layer (dichloromethane layer) and a first aqueous layer. Further, the first organic layer was washed with 400 ml (2 vol) of water to obtain a second organic layer and a second aqueous layer. The first organic layer and the second organic layer were mixed to obtain a combined organic layer. The combined organic layer was distilled under reduced pressure to obtain crude N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide.
Purification:
400 ml (2 vol) of isopropyl alcohol (IPA) was added to the crude N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide followed by heating at 60 °C for 40 minutes under stirring and cooled to 35 °C followed by filtration to obtain a solid comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and a filtrate. The solid obtained was washed with 200 ml (1 vol) isopropyl alcohol and dried at 50 °C in a vacuum tray dryer (VTD) to obtain N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide.
The yield of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide was 85 % to 88 % and purity of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide was 97 Area % to 98 Area % by HPLC.
Step IV: Preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid)
In a 2 litre, 4-necked round bottomed flask, equipped with a condenser thermometer pocket and an agitator, 100 g of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and 400 mL of 1,2-dichloroethane were charged at 25 °C under stirring to obtain a fourth mixture. The fourth mixture was heated to 35 °C followed by adding 200 ml (2 vol) of 15% NaOH solution in a dropwise manner over 30 minutes and maintained at 35 °C under stirring for 3 hours to obtain a fourth reaction mixture.
95.60 g of propargyl bromide (80% solution in Toluene) was added to the fourth reaction mixture over 25 minutes followed by heating to 65 °C and the reaction heating was maintained for 4 hours under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid). The progress of reaction was monitored by HPLC.
Work-up:
The product mixture was cooled to 25 °C followed by adding 400 ml (4 vol) water and stirred for 15 minutes to obtain a first biphasic mixture comprising a first organic layer and an aqueous layer. The first organic layer from the biphasic mixture was separated and washed with water (2 vol x 3) to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture. The first organic layer and second organic layer were combined and concentrated under reduced pressure to obtain a crude product comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid). The crude product was recrystallized (triturated) with 300 ml isopropyl alcohol (3 vol) followed by filtration and drying at 50 °C in a vacuum tray dryer (VTD) to obtain 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).
The yield of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) was 75 % to 80 % and the purity of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) was 98 % (by HPLC).
TECHNICAL ADVANCEMENT
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) that:
• uses low cost reagents;
• is carried out at low temperatures; thereby making the process safe, economical and environment friendly;
• provides high purity and high yield of Mandipropamid;
• has a shorter reaction time and easy purification steps, hence simple; and
• is commercially scalable.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions, and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

, Claims:WE CLAIM:
1. A process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid), said process comprising the following steps:
i. reacting vanillin and nitromethane by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol;
ii. reducing 2-methoxy-4-((E)-2-nitrovinyl)phenol by using a reducing agent in a second fluid medium in an inert atmosphere at a second predetermined temperature for a second predetermined time period under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol;
iii. coupling 4-(2-aminoethyl)-2-methoxyphenol with 4-chloro-a-hydroxy benzene acetic acid in the presence of a catalyst in a third fluid medium at a third predetermined temperature for a third predetermined time period under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide; and
iv. reacting N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and propargyl bromide by using a second base in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).

2. The process as claimed in claim 1, wherein said first base is selected from ammonium acetate and sodium acetate.

3. The process as claimed in claim 1, wherein said reducing agent is selected from H2-Pd/C and H2-Raney-Nickel.

4. The process as claimed in claim 1, wherein said inert atmosphere is selected from nitrogen and argon.

5. The process as claimed in claim 1, wherein said catalyst is selected from boric acid, phosphorus trichloride and phosphorus pentoxide.

6. The process as claimed in claim 1, wherein said second base is selected from the group of bases consisting of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.

7. The process as claimed in claim 1, wherein
• said first fluid medium is acetic acid;
• said second fluid medium is selected from the group consisting of methanol, isopropanol and t-butanol;
• said third fluid medium is selected from dimethylformamide and 1,4 dioxane; and
• said fourth fluid medium is selected from the group consisting of ethylene dichloride, methylene dichloride and ethyl acetate.
8. The process as claimed in claim 1, wherein
• said first predetermined temperature is in the range of 40 °C to 75 °C;
• said second predetermined temperature is in the range of 30 °C to 70 °C;
• said third predetermined temperature is in the range of 90 °C to 125 °C; and
• said fourth predetermined temperature is in the range of 50 °C to 75 °C.

9. The process as claimed in claim 1, wherein
• said first predetermined time period is in the range of 4 hours to 8 hours;
• said second predetermined time period is in the range of 5 hours to 10 hours;
• said third predetermined time period is in the range of 5 hours to 10 hours; and
• said fourth predetermined time period is in the range of 2 hours to 6 hours.

10. The process for the preparation of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) as claimed in claim 1, said process comprising the following steps:
i. reacting vanillin and nitromethane by using ammonium acetate in acetic acid at 55 °C for 5.5 hours under stirring to obtain a first reaction mixture comprising 2-methoxy-4-((E)-2-nitrovinyl)phenol;
ii. reducing 2-methoxy-4-((E)-2-nitrovinyl)phenol by using H2/Pd-C in methanol in nitrogen atmosphere at 50 °C for 7.5 hours under stirring to obtain a second reaction mixture comprising 4-(2-aminoethyl)-2-methoxyphenol;
iii. coupling 4-(2-aminoethyl)-2-methoxyphenol with 4-chloro-a-hydroxy benzene acetic acid in the presence of boric acid in dimethyl formamide at 105 °C for 7.5 hours under stirring to obtain a third reaction mixture comprising N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide; and
iv. reacting N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide and propargyl bromide by using sodium hydroxide in ethylene dichloride at 65 °C for 4 hours under stirring to obtain a product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).

11. The process as claimed in claim 10, wherein
• the mass ratio of vanillin to nitromethane is 1:0.61;
• the mass ratio of 4-(2-aminoethyl)-2-methoxyphenol to 4-chloro-a-hydroxybenzeneacetic acid is 1:0.95; and
• the mass ratio of N-(4-hydroxy-3-methoxyphenethyl)-2-(4-chlorophenyl)-2-hydroxyacetamide to propargyl bromide is 1:0.96.

12. The process as claimed in claim 1, said process further comprising
• cooling said product mixture comprising 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) to a temperature in the range of 20 °C to 30 °C followed by adding water to obtain a biphasic mixture comprising an organic layer and an aqueous layer;
• separating said organic layer and concentrating said organic layer to obtain solids;
• recrystallizing said solids using a solvent followed by filtration and drying at a temperature in the range of 40 °C to 60 °C to obtain 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid).

13. The process as claimed in claim 12, wherein said solvent is an alcohol selected from the group consisting of methanol, isopropanol and t-butanol.

14. The process as claimed in claim 12, wherein the yield of 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide (Mandipropamid) is in the range of 70 % to 75 %.

15. The process as claimed in claim 12, wherein the the purity of 2-(4-chloro-phenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-ynyloxy) acetamide (Mandipropamid) is in the range of 97 % to 99 %.

Dated this 04th day of September, 2024

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
OF R. K. DEWAN & CO.
AUTHORIZED AGENT OF APPLICANT

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT CHENNAI