DESC:FIELD
The present disclosure relates to a process for producing Temephos.
BACKGROUND
Temephos (O,O,O’,O’-Tetramethyl-O,O’-thiodi-p-phenylene phosphorothioate) is an organophosphate larvicide having the molecular formula C16H20O6P2S3. The structural formula of Temephos is given below:

Temephos

Temephos is used to treat water infested with disease-carrying insects, including mosquitoes, midges and black fly larvae. Temephos is a non-systemic organophosphate, affecting the central nervous system of a target organism through inhibition of cholinesterase. In larvae, this results in death before reaching the adult stage.
Further, Temephos is widely used to control the vector-borne disease, dengue fever, in areas where it is endemic. Temephos is also used in the Guinea worm eradication program to kill water fleas that carry guinea worm larvae.
Recently, it has been demonstrated that Temephos exhibits good insecticidal activity along with good residual properties when applied on foliage, without adversely affecting the beneficial insects.
According to World Health Organization (WHO) specifications and evaluations for public health pesticides, Temephos content should not be less than 92.5 %w/w in the pesticide composition. Further, the Temephos contains impurities, such as, iso-Temephos (O-{4-[(4-{[methoxy(methylthio) phosphoryl] oxy}phenyl)thio]phenyl} O,O-dimethyl thiophosphate) and oxon-Temephos (4-({4-[(dimethoxyphosphorothioyl) oxy]phenyl}thio)phenyl dimethyl phosphate) and the content of these impurities should not be more than 1.3 %w/w and 0.3 %w/w, respectively in the pesticide composition. The structural formula of iso-Temephos and oxon-Temephos are as given below:

Iso-Temephos

Oxon-Temephos

The oxon-Temephos impurity can be controlled easily, whereas controlling the iso-Temephos impurity is difficult. It is also observed that the oxon-Temephos and iso-Temephos impurities increase during storage of Temephos at elevated temperatures. According to World Health Organization (WHO), after storage in the temperature range of 40 °C to 43 °C (Stability at Elevated Temperature), the Temephos content should not be less than 92 % relative to the determined content found before storage.
Therefore, there is felt a need for a simple and economic process for production of Temephos, with specified oxon-Temephos and iso-Temephos impurity in the final product.
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 useful alternative.
Another object of the present disclosure is to provide a process for producing Temephos having purity greater than 95 %w/w.
Still another object of the present disclosure is to provide a process for producing Temephos having iso-Temephos content less than 1.2 %w/w.
Yet another object of the present disclosure is to provide a process for producing Temephos wherein the oxon-Temephos and iso-Temephos impurities remain within the specified limits even after storage at elevated temperatures.
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 producing Temephos having a purity greater than 95 %w/w and having iso-Temephos content less than 1.2 %w/w from crude Temephos. The process involves contacting a solution containing dissolved Temephos with modified acidic alumina at a temperature in the range of 25 °C to 35 °C to obtain a treated solution and further concentrating the treated solution to obtain Temephos having purity greater than 95 %w/w and iso-Temephos content of less than 1.2 %w/w.
DETAILED DESCRIPTION
Temephos is widely used to control the vector-borne disease, dengue fever, in areas where it is endemic. Temephos is also used in the Guinea worm eradication program to kill water fleas that carry guinea worm larvae.
Commercially, Temephos is available as an Emulsifiable Concentrate (EC) and as Granules (GR) for vector control.
World Health Organization (WHO) has specified that the Temephos purity should not be less than 92.5 %w/w. Further, the iso-Temephos and oxon-Temephos impurities should not be more than 1.3 %w/w and 0.3 %w/w, respectively.
Therefore, the present disclosure envisages a process for the producing Temephos. The Temephos produced by the process of the present disclosure has purity greater than 95 %w/w. Further, the iso-Temephos content is less than 1.2 %w/w and the oxon-Temephos content is less than 0.1 %w/w.
In an aspect of the present disclosure, the process comprises the following steps:
- dissolving crude Temephos in a solvent to obtain a solution;
- contacting the solution with modified acidic alumina at a temperature in the range of 25 °C to 35 °C to obtain a treated solution; and
- concentrating the treated solution to obtain Temephos having purity greater than 95 %w/w and iso-Temephos content less than 1.2 %w/w.
The solvent can be selected from the group consisting of ethylene dichloride (EDC), toluene, methylene dichloride and the like. In an exemplary embodiment of the present disclosure, the solvent is ethylene dichloride (EDC).
Typically, the ratio of the amount of crude temephos to the amount of the solvent is in the range of 1:1 to 1:20, preferably 1:1 to 1:8.
In an embodiment of the present disclosure, the amount of crude temephos to the amount of the solvent is 1:5.
In an embodiment of the present disclosure, the solution of crude Temephos dissolved in a solvent is passed through a column containing a bed of modified acidic alumina to obtain the treated solution.
Typically, the modified acidic alumina is added to ethylene dichloride to obtain homogenized slurry and the resultant homogenized slurry is used for preparing the column containing the bed of modified acidic alumina.
In another embodiment of the present disclosure, the solution of crude Temephos dissolved in a solvent is stirred with modified acidic alumina to obtain a biphasic mixture containing a liquid phase and a solid phase. The liquid phase is separated from the biphasic mixture to obtain the treated solution.
Typically, the stirring is carried out of a time period ranging from 1 hour to 24 hours.
Typically, the ratio of the crude Temephos to the modified acidic alumina is in the range of 1:2 to 1:10.
The modified acidic alumina used for the production of Temephos can be prepared from acidic alumina and aluminium chloride. A pre-determined amount of acidic alumina is added to a pre-determined amount of water to obtain aqueous acidic alumina slurry. Typically, the ratio of the amount of modified acidic alumina to the amount of water is in the range of 1:1 to 1:5.
Next, a pre-determined amount of aqueous solution of aluminium chloride (20 %w/v to 30 %w/v) is added to the aqueous acidic alumina slurry. The so obtained mixture is refluxed for a time period in the range of 1 hour to 3 hours to obtain a biphasic mixture, containing a solid phase and a liquid phase. The solid phase containing the modified acidic alumina is separated from the biphasic mixture i and dried under reduced pressure (under vacuum) at a temperature in the range of 150 °C to 250 °C for a time period in the range of 7 hours to 10 hours to obtain the modified acidic alumina.
The present disclosure is further illustrated herein below with the help of the following experiments. The experiments 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 experiments should not be construed as limiting the scope of embodiments herein. These laboratory scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.
Experimental Details:
Crude Temephos comprising 93.34 %w/w of Temephos, 5.2 %w/w of iso-Temephos and 0.1 %w/w of oxon-Temephos was used for all the experiments.
The above mentioned crude Temephos was dissolved in EDC (referred to as Solution-A hereinafter) to obtain 20 %w/v solution and used for all the experiments.
Experiment 1A: Preparation of modified acidic alumina
200 g acidic alumina was stirred in 400 ml water to obtain an aqueous acidic alumina slurry. Aqueous solution of aluminium chloride (26 g AlCl3 dissolved in 100 ml water) was added to the aqueous acidic alumina slurry and stirred to obtain a mixture. The mixture was then refluxed for 2 hours. The refluxed mixture was then cooled to room temperature and filtered. The residual cake was dried under vacuum oven at 200 °C for 8 hours to obtain the modified acidic alumina.
Experiment 1B: Preparation of column of modified acidic alumina
100 g of the modified acidic alumina, was added to ethylene dichloride to obtain a homogenized slurry, and the slurry was packed in a column having a diameter of 34 mm.
Experiment 2: Production of Temephos in accordance with the process of the present disclosure
500 ml of Solution A was passed through the column of homogenized slurry of modified acidic alumina, prepared in experiment 1. The temperature of the column was maintained at 30 °C. The eluent obtained was concentrated to obtain 90 g Temephos. HPLC analysis of the isolated Temephos was carried out, the Temephos content was found to be 95.2 %w/w, the iso-Temephos impurity was found to be 0.17 %w/w and oxon-Temephos impurity was found to be 0.1 %w/w by area normalization.
Experiment 3: Stability study of Temephos produced in accordance with the process of the present disclosure
Experiment 2 was repeated and the eluent obtained was once again passed through a fresh column containing homogenized slurry of modified acidic alumina. The eluent was concentrated to yield 92 g Temephos. HPLC analysis of isolated Temephos showed Temephos content = 98.4 %w/w and the impurities of iso-Temephos = 0.06 %w/w and oxon-Temephos = 0.04 %w/w by area normalization.
The isolated Temephos was stored at 45 °C for 14 days (accelerated storage stability studies). The HPLC analysis of Temephos of the samples subjected to accelerated storage study was found to be: Temephos content = 98.3 %w/w and the impurities of iso-Temephos = 0.18 %w/w and oxon-Temephos = 0.03 %w/w, by area normalization.
Thus, it was found that the Temephos produced by the process of the present disclosure, was stable under accelerated storage conditions, as per the WHO norms.
Experiment 4: Stability study of EC formulations comprising Temephos produced in accordance with the process of the present disclosure
Experiment 2 was repeated, however, the column was prepared using 200 g of modified acidic alumina. The diameter of the column was 34 mm. The solution was passed through the column at 30 °C. The eluent was concentrated to yield 91 g of Temephos, having 98.3 % w/w Temephos and iso-Temephos impurity < 0.09 %w/w and oxon-Temephos < 0.05 %w/w, by area normalization.
The Temephos was formulated as emulsifiable concentrate (EC) and 50 % EC solution was subjected to accelerated storage stability studies. The iso and oxon-Temephos content in 50 % EC were found to be 0.38 %w/w and 0.05 %w/w, respectively, indicating that the iso and oxon impurities did not increase above the specification values accelerated storage stability studies.
It was found that the Temephos produced by the process of the present disclosure and formulated as emulsifiable concentrate (EC), was stable under accelerated storage conditions, as per the WHO norms
Experiment 5: Production of Temephos in accordance with the process of the present disclosure
500 ml of Solution A was stirred with 200 g of modified acidic alumina at 30°C for 12 hours. The modified acidic alumina was separated by filtration. The filtrate obtained was concentrated and analyzed. The yield of Temephos was 91 g.
HPLC analysis of isolated Temephos showed the Temephos content = 97.05 %w/w and iso-Temephos impurity = 0.14 %w/w and oxon-Temephos < 0.01 %w/w, by area normalization.
When the eluent obtained in the above experiments 2 to 4 are passed through a fresh column containing a bed of modified acidic alumina in EDC having the same dimensions, a further increase in the Temephos content was observed along with a reduction in the oxon-Temephos and iso-Temephos impurities. The HPLC analysis of Temephos subjected to accelerated storage stability studies shows that there was no significant reduction in the Temephos content. The oxon-Temephos and iso-Temephos impurities were also within the specified limits. Similar results were observed even when different amounts of modified acidic alumina were used.
Comparative Experiment 6
500 ml of Solution-A was stirred with 2 g of neutral alumina, at 30 °C for 12 hours. The neutral alumina was then separated by filtration, the filtrate was concentrated and analyzed. There was no improvement in the Temephos content, further, a reduction in oxon-Temephos and iso-Temephos impurities was also not observed.
Comparative Experiment 7
The process of comparative experiment 6 was repeated with acidic alumina, in place of neutral alumina. There was no improvement in the Temephos content, further, a reduction in oxon-Temephos and iso-Temephos impurities was also not observed.
Comparative Experiment 8
The process of comparative experiment 6 was repeated with basic alumina, in place of neutral alumina. There was no improvement in the Temephos content, further, a reduction in oxon-Temephos and iso-Temephos impurities was also not observed.
From the above comparative experiments 6, 7 and 8, it is clear that a lower ratio of crude Temephos to the acidic alumina is ineffective in producing Temephos having the desired purity.
The Temephos produced by the process of the present disclosure has purity greater than 95 %w/w, also the oxon-Temephos and iso-Temephos impurities are within the specified limits, even after being subjected to accelerated storage stability conditions.
TECHNICAL ADVANCEMENTS AND ECONOMICAL SIGNIFICANCE
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for the production of Temephos having high purity and wherein the oxon-Temephos and iso-Temephos impurities are within the specified limits, as per the WHO guidelines. Further, the Temephos produced by the process of the present disclosure is stable under accelerated storage conditions.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
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.
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:1. A process for producing Temephos having a purity greater than 95 %w/w and having iso-Temephos content less than 1.2 %w/w from crude Temephos, said process comprising the following steps:
- dissolving said crude Temephos in a solvent to obtain a solution;
- contacting said solution with modified acidic alumina at a temperature in the range of 25 °C to 35 °C to obtain a treated solution; and
- concentrating said treated solution to obtain Temephos having purity greater than 95 %w/w and iso-Temephos content of less than 1.2 %w/w.

2. The process as claimed in claim 1, wherein the content of oxon-Temephos in said Temephos having purity greater than 95 %w/w, is less than 0.1 %w/w.

3. The process as claimed in claim 1, wherein said solvent is selected from the group consisting of ethylene dichloride, toluene and methylene dichloride.

4. The process as claimed in claim 1, wherein the step of contacting involves passing said solution through a column containing a bed of said modified acidic alumina to obtain said treated solution.

5. The process as claimed in claim 1, wherein the step of contacting involves stirring said solution with said modified acidic alumina for 1 to 24 hours, to obtain a biphasic mixture containing a liquid phase and a solid phase and separating said liquid phase from said biphasic mixture to obtain said treated solution.
6. A process for preparing the modified acidic alumina used for the production of Temephos having a purity greater than 95 %w/w and having iso-Temephos content less than 1.2 %w/w as claimed in claim 1, said process comprising the following steps:
- adding acidic alumina to water to obtain an aqueous acidic alumina slurry, wherein the ratio of the amount of acidic alumina to the amount of water is in the range of 1:1 to 1:5;
- adding 20 % w/v to 30 %w/v aqueous solution of aluminium chloride to said aqueous acidic alumina slurry to obtain a mixture and heating said mixture under reflux for a time period in the range of 1 hour to 3 hours, followed by cooling to obtain a biphasic mixture containing a solid phase and a liquid phase; and
- separating the solid phase from the biphasic mixture and drying the solids under reduced pressure at a temperature in the range of 150 °C to 250 °C for 7 hours to 10 hours to obtain the modified acidic alumina.