Description:TITLE OF THE INVENTION: A PROCESS OF SYNTHESISING FLUMETRALIN AND A FORMULATION THEREOF
FIELD OF THE INVENTION
The present disclosure is generally related to flumetralin. Particularly, the present disclosure is related to a process of synthesising flumetralin. More particularly, the present disclosure is related to: a process of synthesising flumetralin; and a formulation thereof.
BACKGROUND OF THE INVENTION
Processes for synthesising flumetralin are known in the art. However, existing processes suffer from various drawbacks, including, but not limited to: complex nature (involve multiple steps); and/or low yields (maximum yields obtained are only about 80%).
There is, therefore, a need in the art, for: a process of synthesising flumetralin; and a formulation thereof, which overcome the aforementioned drawbacks and shortcomings.
SUMMARY OF THE INVENTION
A process of synthesising flumetralin, and a formulation thereof, are disclosed. Said process broadly comprises two steps. In a first step, 1-chloro-2-(chloromethyl)-3-fluorobenzene is mixed with an aqueous ethanamine solution, to obtain N-(2-chloro-6-fluorobenzyl) ethanamine. In a second step, 4-chloro-3,5-dinitrobenzotrifluoride is mixed with the N-(2-chloro-6-fluorobenzyl) ethanamine, to obtain flumetralin.
The disclosed formulation broadly comprises: synthesised flumetralin (or flumetralin); polysorbate 20 as a thickening agent; polysorbate 80 as a dispersion agent; glycerol as an anti-freezing agent; liquid lecithin as an emulsifier; and water.
The disclosed process (and/or formulation) offers at least the following synergistic advantages and effects: is simple (involves only two steps); offers high yields (maximum yields obtained are about 90% to about 94%); and/or is non-toxic.
DETAILED DESCRIPTION OF THE INVENTION
Throughout this specification, the use of the words “comprise” and “include”, and variations, such as “comprises”, “comprising”, “includes”, and “including”, may imply the inclusion of an element (or elements) not specifically recited. Further, the disclosed embodiments may be embodied, in various other forms, as well.
Throughout this specification, the use of the word “synthesis”, and its variations, is to be construed as: “produce; manufacture; and/or the like”.
Throughout this specification, the use of the phrase “synthesised formulation” is to be construed as: “a formulation that is synthesised from flumetralin, with said flumetralin being synthesised as per the process disclosed in the present disclosure, for controlling tobacco suckers”.
Throughout this specification, the use of the phrase “synthesised flumetralin” is to be construed as: “flumetralin that is synthesised as per the process disclosed in the present disclosure, for controlling tobacco suckers”.
Throughout this specification, the use of the acronym “K2CO3” is to be construed as: “potassium carbonate”.
Throughout this specification, the use of the acronym “DMF” is to be construed as: “N,N-dimethylformamide”.
Throughout this specification, the use of the acronym “SM1” is to be construed as: “starting material 1”.
Throughout this specification, the use of the acronym “SM2” is to be construed as: “starting material 2”.
Throughout this specification, the use of the acronym “SM3” is to be construed as: “starting material 3”.
Throughout this specification, the use of the acronym “INT-1” is to be construed as: “intermediate-1”.
Throughout this specification, the use of the acronym “LC-MS” is to be construed as: “liquid chromatography-mass spectrometry”.
Throughout this specification, the use of the acronym “GC-MS” is to be construed as: “gas chromatography-mass spectrometry”.
Throughout this specification, the use of the acronym “TLC” is to be construed as: “thin layer chromatography”.
Throughout this specification, the disclosure of a range is to be construed as being inclusive of: the lower limit of the range; and the upper limit of the range.
Throughout this specification, the words “the” and “said” are used interchangeably.
Also, it is to be noted that embodiments may be described as a method. Although the operations, in a method, are described as a sequential process, many of the operations may be performed in parallel, concurrently, or simultaneously. In addition, the order of the operations may be re-arranged. A method may be terminated, when its operations are completed, but may also have additional steps.
A process of synthesising flumetralin (may also be referred to as “process”), and a formulation thereof for controlling tobacco suckers (may also be referred to as “formulation”) are disclosed. Said flumetralin was synthesised, as follows:
Synthesis of Flumetralin
About 1 mmol of 1-chloro-2-(chloromethyl)-3-fluorobenzene (also referred to as “SM1”) was added to about 5 mmol (5 times the volume of SM1) of DMF, to obtain a mixture. About 1.5 mmol of K2CO3 was added to the mixture and stirred for about 5 minutes, to obtain a solution. Said 1-chloro-2-(chloromethyl)-3-fluorobenzene and said DMF were in a ratio of about 1:5. Said 1-chloro-2-(chloromethyl)-3-fluorobenzene and said K2CO3 were in a ratio of about 1:1.5.
About 70% of ethanamine (also referred to as “SM2”) was added to water (about 30%), to obtain an aqueous ethanamine solution. Said ethanamine and said water were in a ratio of about 2.3:1. The aqueous ethanamine solution was added to the solution from the previous step, and stirred continuously at room temperature (RT) for about 1 hour, to obtain another solution. The reaction was monitored by LC-MS and TLC, until completion.
Once the reaction was completed, about 30 mmol of n-hexane (about 30 times the volume of said another solution, from the previous step) was added to said another solution, and washed (about 4 to about 5 times), to obtain a crude extract. The crude extract was then concentrated (for example, rotary evaporator), to obtain a light brown liquid. The light brown liquid was N-(2-chloro-6-fluorobenzyl) ethanamine (also referred to as “INT-1” or intermediate-1), as illustrated, in the equation below.

About 3 mmol of the intermediate-1 was added to about 3 mmol of said potassium carbonate and 5 mmol of said DMF, followed by addition of about 0.85 mmol of 4-chloro-3,5-dinitrobenzotrifluoride (also referred to as “SM3”), to obtain another mixture. Said another mixture was stirred continuously at about 90οC to about 100οC for about 2 hours. The reaction was monitored by TLC, until said INT-1 or said SM3 was observed (indicating incomplete reaction), and stirred for about another 30 minutes to about 1 hour, to obtain a reaction mixture.
Said intermediate-1 and said potassium carbonate were in a ratio of about 1:1. Said intermediate-1 and said DMF were in a ratio of about 0.6:1. Said intermediate-1 and said 4-chloro-3,5-dinitrobenzotrifluoride were in a ratio of about 3.5:1.
The reaction mixture was then filtered, to filter salts and to obtain a filtrate. Crushed ice was added to the filtrate, followed by addition of about 20% of ethyl acetate, to obtain a filtrate solution. The filtrate solution was washed with about 200 mL of said n-hexane (about four times), followed by concentrating at about 58°C to remove said DMF, to obtain a gummy brown liquid.
The gummy brown liquid was then cooled to room temperature, to obtain a cooled liquid. About 200 mL of n-pentane was added to the cooled liquid, and stirred for about 30 minutes to about 45 minutes, to obtain a solid. The solid was filtered, washed with said n-hexane (about 2 times), and dried, to obtain a yellow solid powder, flumetralin (as illustrated in the equation below).

Synthesis of Formulation
The disclosed formulation broadly comprised: synthesised flumetralin (or flumetralin); a thickening agent (polysorbate 20); a dispersion agent (polysorbate 80); an anti-freezing agent (glycerol); an emulsifier (liquid lecithin); and water.
Said synthesised flumetralin and said polysorbate 20 were in a ratio of about 8.75:1. Said synthesised flumetralin and said polysorbate 80 were in a ratio of about 0.875:1. Said synthesised flumetralin and said glycerol were in a ratio of about 3.5:1. Said synthesised flumetralin and said liquid lecithin were in a ratio of about 0.44:1. Said synthesised flumetralin and said water were in a ratio of about 1.12:1.
About 17.5% (w/v) of said synthesised flumetralin, about 2% (v/v) of said polysorbate 20, about 20% (v/v) of said polysorbate 80, about 5% (v/v) of said glycerol, about 40% (v/v) of said liquid lecithin, and about 15.5% (v/v) of said water were mixed, and stirred well, to obtain said formulation.
Toxicity Analyses
The synthesised formulation (about 10 mL) was sprayed on tobacco suckers (treated plants), which were then harvested to analyse maximum residue levels (MRL), using GC-MS. The results indicated that the treated plants had undetectable levels (less than about 0.01 mg/kg) of the synthesised flumetralin, confirming that the treated plants did not contain residual flumetralin and that the synthesised formulation was non-toxic.
The disclosed process (and/or formulation) offers at least the following synergistic advantages and effects: is simple (involves only two steps); offers high yields (maximum yields obtained are about 90% to about 94%); and/or is non-toxic.
It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements, without deviating from the spirit and the scope of the disclosure, may be made, by a person skilled in the art. Such modifications, additions, alterations, and improvements, should be construed as being within the scope of this disclosure. , C , Claims:1. A two-step process of synthesising flumetralin, for controlling tobacco suckers, comprising steps of:
a) mixing 1-chloro-2-(chloromethyl)-3-fluorobenzene with N,N-dimethylformamide, to obtain a mixture;
b) adding potassium carbonate to the mixture, obtained in step a), and stirring for 5 minutes, to obtain a solution; with: said 1-chloro-2-(chloromethyl)-3-fluorobenzene and said N,N-dimethylformamide being a ratio of 1:5; and said 1-chloro-2-(chloromethyl)-3-fluorobenzene and said potassium carbonate being in a ratio of 1:1.5;
c) adding ethanamine to water, to obtain an aqueous ethanamine solution; with: ratio of said ethanamine to said water being 2.3:1;
d) adding the aqueous ethanamine solution, obtained in step c), to the solution obtained in step b), stirring continuously at room temperature, for 1 hour, to obtain another solution;
e) washing said another solution, obtained in step d), with n-hexane, to obtain a crude extract;
f) concentrating the crude extract, obtained in step e), to obtain a light brown liquid, said light brown liquid being N-(2-chloro-6-fluorobenzyl) ethanamine;
g) adding said N-(2-chloro-6-fluorobenzyl) ethanamine to said potassium carbonate and said N,N-dimethylformamide, followed by addition of 4-chloro-3,5-dinitrobenzotrifluoride, to obtain another mixture; with:
ratio of said N-(2-chloro-6-fluorobenzyl) ethanamine to said potassium carbonate being 1:1;
ratio of said N-(2-chloro-6-fluorobenzyl) ethanamine to said N,N-dimethylformamide being 0.6:1; and
ratio of said N-(2-chloro-6-fluorobenzyl) ethanamine to said 4-chloro-3,5-dinitrobenzotrifluoride being 3.5:1;
h) stirring said another mixture, obtained in step g), at 90οC to 100οC, to obtain a reaction mixture;
i) filtering the reaction mixture, obtained in step h), to filter salts and to obtain a filtrate;
j) adding ethyl acetate to the filtrate, obtained in step i), to obtain a filtrate solution;
k) washing said filtrate solution, obtained in step j), with said n-hexane, and concentrating, to obtain a gummy brown liquid;
l) cooling the liquid, obtained in step k), to room temperature, to obtain a cooled liquid;
m) adding n-pentane to the cooled liquid, obtained in step l), and stirring for 30 minutes to 45 minutes, to obtain a solid; and
n) filtering the solid, obtained in step m), washing with said n-hexane, and drying, to obtain a yellow solid powder.
2. The two-step process of synthesising flumetralin, for controlling tobacco suckers, as claimed in claim 1, wherein:
concentration of said 1-chloro-2-(chloromethyl)-3-fluorobenzene is 1 mmol;
concentration of said N,N-dimethylformamide, in step a), is 5 mmol; and
concentration of said potassium carbonate, in step a), is 1.5 mmol.
3. The two-step process of synthesising flumetralin, for controlling tobacco suckers, as claimed in claim 1, wherein: concentration of said ethanamine is 70%; and concentration of said water is 30%.
4. The two-step process of synthesising flumetralin, for controlling tobacco suckers, as claimed in claim 1, wherein: concentration of said n-hexane is 30 mmol.
5. The two-step process of synthesising flumetralin, for controlling tobacco suckers, as claimed in claim 1, wherein:
concentration of said N-(2-chloro-6-fluorobenzyl) ethanamine is 3 mmol;
concentration of said potassium carbonate, in step g), is 3 mmol;
concentration of said N,N-dimethylformamide, in step g), is 5 mmol; and
concentration of said 4-chloro-3,5-dinitrobenzotrifluoride is 0.85 mmol.
6. A formulation, for controlling tobacco suckers, comprising: flumetralin; polysorbate 20; polysorbate 80; glycerol; liquid lecithin; and water, with:
said flumetralin and said polysorbate 20 being in a ratio of 8.75:1;
said flumetralin and said polysorbate 80 being in a ratio of 0.875:1;
said flumetralin and said glycerol being in a ratio of 3.5:1;
said flumetralin and said liquid lecithin being in a ratio of 0.44:1; and
said flumetralin and said water being in a ratio of 1.12:1.
7. The formulation, for controlling tobacco suckers, as claimed in claim 6, wherein:
concentration of said flumetralin is 17.5% (w/v);
concentration of said polysorbate 20 is 2% (v/v);
concentration of said polysorbate 80 is 20% (v/v);
concentration of said glycerol is 5% (v/v);
concentration of said liquid lecithin is 40% (v/v); and
concentration of said water is 15.5% (v/v).