DESC:Field of the Disclosure

The present disclosure relates to a process for preparing an Anilofos and its analogues.

Background

Anilofos is chemically known as O, O- dimethyl-S-4-chloro isopropylbenzene carbamoyl -N- dimethyl phosphorothioate, a phosphorodithioate ester herbicide, mainly used in rice fields for controlling annual grass and sedge weeds. Anilofos is a pre-emergence and early post-emergence selective herbicide used for the control of annual grasses, sedges and some broad-leaved weeds in transplanted and direct seeded rice. Anilofos is absorbed by the weeds primarily through the roots and to some extent through newly emerging shoots and young leaves. The mechanism of action of Anilofos lies in acting on the meristematic tissues of weeds that severely affects the cell division and cell elongation.

Various conventional methods have been developed for the synthesis of Anilofos owing to its wide popularity. However, the previously described methods are associated with certain drawbacks such as poor stability and product purity. Further, most of the conventional methods employ huge quantities of expensive reagents that increase the expenditure associated with the processes along with jeopardizing the environmental sanctity.
Therefore, there is felt a need for simple and cost effective process for the preparation of Anilofos with high purity and stability.

Objects

Some of the objects of the present disclosure, which at least one embodiment is adapted to provide, are described herein below:
? It is an object of the present disclosure to provide a process for the preparing Anilofos and its analogues.
? It is another object of the present disclosure to provide a process for the preparation of anilofos and its analogues, which is rapid, stable, economic and environment friendly.
? It is still another object of the present disclosure to provide a process that gives high yield.
? It is yet another object of the present disclosure to provide a process that yields high purity product.
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 provides a simple and economic process for preparing a compound (Anilofos) of Formula 1 and its analogues.
The process comprising the step of i) reacting a compound of Formula 2 and a compound of Formula 3 to obtain a compound of Formula 4;

wherein, X1 and X2 are selected from the group that includes but is not limited to chlorine, bromine and iodine, preferably chlorine; X is selected from the group that includes but is not limited to chlorine, bromine and iodine, preferably chlorine; n is an integer in the range of 1-5, preferably 1; and R is selected from the group consisting of Hydrogen and branched or un-branched C1-C10 alkyl groups,

ii) alkoxylating phosphorous pentasulfide (P2S5) with a compound of Formula 5 to obtain a compound of Formula 6;

iii) reacting compound of Formula 6 with the base to obtain a compound of Formula 7 (alkoxylated phosphorous pentasulfide base); and

iv) reacting the compound of Formula 4 with alkoxylated phosphorous pentasulfide base of Formula 7 to obtain a compound of Formula 1.

Typically, R3 is selected from the group that includes but is not limited to linear or branched C1-C5 alkyl groups.

Brief decription of drawings:

Figure 1 illustrates the schematic represnetation of reactions in accordance with the present disclosure.

Detailed Description

Anilofos (S-[2-[(4-chlorophenyl) (1-methylethyl) amino]-2-oxoethyl] O, O-dimethyl phosphorodithioate) and its analogues are active chemicals of commercial grade herbicide. The previously suggested method provides less stable and low purity anilofos and its analogues. Further, the conventional methods are costly as it employs comparatively high quantities of expensive reagents that increase the cost of the process.

Accordingly, the process in accordance with the present disclosure provides a simple and cost effective for the preparation of anilofos and its analogues that have high purity and stability.

In accordance with the present disclosure there is provided a process for the preparation of a compound of Formula 1. The structure of the compound of Formula 1 is presented herein below.

Formula 1
X in the Formula 1 is selected from the group consisting of chlorine, bromine and iodine, preferably chlorine. n is an integer in the range of 1-2, preferably 1. R is selected from the group consisting of Hydrogen and branched or un-branched C1-C10 alkyl groups. R3 is independently selected from the group consisting of linear or branched C1-C5 alkyl groups.

In one embodiment of the present disclosure, the compound of Formula 1 is Anilofos.
In the first step of the process of present disclosure, a compound of Formula 2 is reacted with a compound of Formula 3 to obtain a compound of Formula 4. The reaction is called amidization of the compound of Formula 2. The reaction is carried out at a temperature ranging from 30-80oC.

The compound of Formula 2 used in the process of present disclosure includes but is not limited to 4-chloroisopropyl aniline, 4-bromoisopropyl aniline and 4-iodoisopropyl aniline. Preferably, 4-chloroisopropyl aniline (IPPCA) is employed as compound of Formula 2. The purity of Formula 2 used in the process of present disclosure ranges from 99.0 to 99.9%.

The compound of Formula 3 used in the process of present disclosure includes but is not limited to chloroacetyl chloride, bromoacetyl chloride, iodoacetyl chloride, bromoacetyl boomide, iodoacetyl iodide, bromoacetyl iodide and iodoacetyl bromide. Preferably chloroacetyl chloride is employed as compound of Formula 3. The purity of Formula 3 used in the process of present disclosure ranges from 99.0 to 99.9%.

The reaction scheme is represented in Figure 1.
The structures of the compounds of Formula 2, 3 and 4 are presented herein below.
X1 and X2 are selected from the group that includes but is not limited to chlorine, bromine and iodine, preferably chlorine. X is selected from the group that includes but is not limited to chlorine, bromine and iodine, preferably chlorine. n is an integer in the range of 1-5, preferably 1. R is selected from the group consisting of Hydrogen and branched or un-branched C1-C10 alkyl groups.

The compound of Formula 4 used in the process of present disclosure includes but is not limited to 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide, 2-bromo-N-(4-chlorophenyl)-N-isopropylacetamide, 2-iodo-N-(4-chlorophenyl)-N-isopropylacetamide, 2-bromo-N-(4-bromophenyl)-N-isopropylacetamide, 2-iodo-N-(4-iodophenyl)-N-isopropylacetamide, 2-bromo-N-(4-iodophenyl)-N-isopropylacetamide and 2-iodo-N-(4-bromophenyl)-N-isopropylacetamide.

The purity of compound of Formula 4 used in the process of present disclosure ranges from 97.0 to 99.0%.

In one embodiment of the present disclosure chloroacetyl chloride (Formula 3) is reacted with 4-chloroisopropyl aniline (Formula 2) at a temperature ranging from 30-80oC to obtain 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide of Formula 4.

In the second step of the process of present disclosure, Phosphorus pentasulfide (P2S5) is reacted with a compound of Formula 5 to undergo alkoxylation in the presence of at least one first reaction medium to obtain a compound of Formula 6. The reaction is carried out at a temperature ranging from 10-50oC. The reaction scheme is given in Figure 1.

The structures of phosphorous pentasulfide, Formula 5 and Formula 6 are represented herein below:

R3 of Formula 5 and Formula 6 is selected from the group that includes but is not limited to linear or branched C1-C5 alkyl groups. The compound of Formula 5 of the present disclosure is selected from the group consisting of alcohols containing C1-C5 alkyl groups. In one embodiment alcohol (Formula 5) used in the process of present disclosure is methanol. The amount of alcohol used in the process of present disclosure ranging from 4 to 6 moles with respect to moles of P2S5.

Alcohol (Formula 5) used in the step of alkoxylation is taken in an amount sufficient to react with P2S5. This prevents the formation of polysulfide impurities during the reaction which affects the final product yield and purity. In one embodiment, the quantity of the alcohol is more than that required to sufficiently react with P2S5. The molar ratio of P2S5 and the alcohol used in the process of present disclosure ranges from 1: 4 to 1: 6.

The first reaction medium of the present disclosure is selected from the group consisting of polar and non-polar solvents. The reaction medium includes but is not limited to dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, dimethylformamide (DMF), acetone, acetonitrile, dimethyl sulfoxide (DMSO), ethanol, methanol, xylene, benzene, ethylbenzene, hexane, cyclohexane, toluene and mixtures thereof.

The alkoxylated product (Formula 6 - dialkoxy thiophosporic acid) is obtained by the reaction between phosphorous pentasulfide and alcohol at a temperature ranging from 10-50oC upon removal of hydrogen sulfide.

In one embodiment of the present disclosure phosphorous pentasufide is reacted with methanol (Formula 5) at a temperature ranging from 10-50oC to obtain dimethoxy thiophosporic acid (Formula 6).

In third step of the process of present disclosure, the compound of Formula 6 obtained in second step of the present disclosure is treated with at least one aqueous base to provide a compound of Formula 7.

R3 in Formula 6 and 7 of the present disclosure is selected from the group consisting of linear or branched C1-C5 alkyl groups, and B+ is a cationic part of the base.
The base used in the process of the present disclosure includes but is not limited to ammonia, ammonium hydroxide, sodium hydroxide, and potassium hydroxide. B+ in the compound of Formula 7 includes but is not limited to NH3+, Na+ and K+.

In the fourth step of the process of present disclosure, the compound of Formula 4 of the present disclosure is condensed with Formula 7 of the present disclosure in the presence of at least one second reaction medium to obtain a compound of Formula 1.

The second reaction medium of the present disclosure is selected from polar and non-polar solvents. The second reaction medium includes but is not limited to dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, dimethylformamide (DMF), acetone, acetonitrile, dimethyl sulfoxide (DMSO), ethanol, methanol, xylene, benzene, ethylbenzene, hexane, cyclohexane, toluene and mixtures thereof. The first reaction medium and the second reaction medium of the present disclosure may or may not be the same. The step of condensation of the compound of Formula 4 is carried out at a temperature ranging from 20 to 50oC.

The proportion of compound of Formula 4 and the compound of Formula 7 of the present disclosure ranging from 1:1 to 1:1.5. Significantly, the step of condensation is carried out in a shorter time span, as compared to previously known process.

Further, the product obtained in accordance with the process of the present disclosure has more than 85-90 % yields, with purity ranging from 95-99%.

According to the present disclosure, heat precipitation procedure is not carried out during the reaction procedure. Therefore, a potential danger of the decomposition of the product under heat is avoided and hence product yield and quality are improved. The preparation method of herbicide anilofos provided by the present disclosure has advantages of simple process to obtain high product yield with high purity. The process of the present disclosure is safe and hence environment friendly, therefore is suitable for industrial level production.
The present disclosure is further described in light of the following non-limiting examples which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure.

Example 1:

Preparation of Formula 4 of the present invention disclosure:

170gm of 4-chloro-isopropyl aniline (IPPCA) was condensed with 124gm of chloroacetyl chloride at 74-75oC in a suitable solvent media to obtain 243gm of 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide.

Preparation of Formula 7 of the present invention disclosure:

1 gm mole of P2S5 in 270 ml of xylene was reacted with 5.0 m/m methanol at 44-45oC till total hydrogen sulfide evolved. The dissolved H2S was vacuum pulled and the first reaction mixture comprising DMTA was neutralized to pH 9.5-10.5 by treating with 8 -10N NaOH to obtain 162-163 gm of sodium salt of DMTA in the form of a solution.

Reaction of Formula 4 and Formula 7:

1.0 gm mole of 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide was charged into a 4-neck RB flask containing 400 ml of n-Hexane with overhead stirring at 28-32oC. Into this mass, 1.2 gram mole of freshly prepared Na-DMTA solution of 3.9N was added over 1 hour maintaining the temperature at 28-32oC. The reaction was maintained at the same temperature under stirring for 15 hours, till anilide content in the reaction mass becomes less than 1.0%. The reaction progress was monitored by HPLC/GLC. The obtained reaction mass was white colored slurry into which 0.1 mole of 8-10N NaOH solution was added and upon addition the slurry was cooled to 25oC and filtered to obtain the product. The filtered product (cake) was washed with water to make it free of alkalinity, followed by 100 ml of n-Hexane wash. The hexane wet cake was dried at 54-55oC under vacuum till constant weight. The yield obtained was 330 gm with 97% of purity.

Example 2:

The compound of Formula 4(2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide) and Formula 7(NH4-DMTA) was prepared by the method as provided in example 1 except for preparation of Formula 7, ammonia was used as a base to obtain NH4-DMTA.
1.0 gm mole of 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide was charged into a 4-neck RB flask containing 400 ml of n-Hexane with overhead stirring at 28-32oC. 1.2 gm mole of freshly prepared NH4-DMTA solution of 3.8N was added in the reaction mixture over 1 hour maintaining temperature at 28-32oC. The stirring was carried out for 18 hours at the same temperature till anilide content in the reaction mass becomes less than 1.0%. The reaction progress was monitored by HPLC/GLC. The obtained reaction mass was a white colored slurry, into which 0.1 mole of 8-10N NaOH solution was added followed by cooling it to 25oC and filtration. The filtered cake was washed with water to make it free of alkalinity followed by 100ml of n-Hexane wash. The hexane wet cake was dried at 54-55oC under vacuum till constant weight. The yield obtained was 305 gm with 96.5% of purity.

Example 3:

The compound of Formula 4(2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide) and Formula 7(Na-DMTA) was prepared by the method as provided in example 1
1.0 gm mole of 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide was charged into a 4-neck RB flask containing 200 ml of n-Hexane with overhead stirring at 28-32oC. Into this mass, 1.2 gm mole of freshly prepared Na-DMTA solution of 3.9N was added over 1 hour maintaining a temperature ranging from 28-32oC. The reaction was stirred at the same temperature for 12 hours, till anilide content in the reaction mass becomes less than 1.0 %. The reaction progress was monitored by HPLC/GLC. The obtained reaction mass was a white colored slurry into which 0.1mole of 8-10N NaOH solution and 200ml of n-Hexane was added and then further cooled to 22-23oC followed by filtering the slurry. The filtered cake was washed with water to make it free of alkalinity followed by 100ml of n-Hexane wash. The hexane wet cake was dried at 54-55oC under vacuum till constant weight. The yield obtained was 320gm with 96.7% of purity.

Example 4:

The compound of Formula 4(2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide) and Formula 7(Na-DMTA) was prepared by the method as provided in example 1.
1.0 gm mole of 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide was charged into a 4-neck RB flask containing 100 ml of cyclohexane with overhead stirring at 28-35oC. 1.2 gm mole of freshly prepared Na-DMTA solution of 4.1N was added in the reaction mixture over 1 hour maintaining at a temperature ranging from 28-32oC. The stirring of the reaction was carried out at the same temperature for 18 hours, till anilide content in the reaction mass becomes less than 1.0 %. The reaction progress was monitored by HPLC/GLC. The obtained reaction mass was a white colored slurry into which 0.1 mole of 8-10N NaOH solution was added and then cooled to 18-20oC and filtered. The filtered cake was washed with water to make it free of alkalinity followed by 50ml of cyclohexane wash. The hexane wet cake was dried at 54-55oC under vacuum till constant weight. The yield obtained was 322 gm with 97% of purity.

Example 5:

The compound of Formula 4 i. e 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide and Formula 7(NH4-DMTA) was prepared by the method as provided in example 3.
1.0 gram mole of 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide was charged into a 4-neck RB flask containing 100ml of cyclohexane with overhead stirring at 28-35oC to obtain a mass. 1.2gram mole of freshly prepared NH4-DMTA solution of 3.8N was added in the obtained mass over 1 hour maintaining temperature at 28-32oC. The stirring of the reaction was maintained at a temperature of 28-35oC for 17 hours, till anilide content in the reaction mass becomes less than 1.0 %. The reaction was monitored by HPLC/GLC. The obtained reaction mass was a white colored slurry, into which 0.1 mole of 8-10N NH4OH solution was added and then cooled to a temperature of 18-20oC. After cooling, the slurry was filtered through Buchner funnel. The filtered cake was washed with water to make it free of alkalinity followed by 50 ml of cyclohexane wash. Cake was dried at 54-55oC under vacuum till constant weight. The yield obtained was 215 gm with 96.6% of purity.

The examples 1-5 are summarized in the Table 1 as given below:

Example no Formula 4 Formula 7 Second reaction medium Reaction time Purity of the compound of Formula 1
Example 1 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide Na-DMTA n-Hexane 15 hours 97%
Example 2 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide NH4-DMTA n-Hexane 18 hours 96.50%
Example 3 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide Na-DMTA n-Hexane 12 hours 96.70%
Example 4 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide Na-DMTA Cyclohexane 18 hours 97%
Example 5 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide NH4-DMTA Cyclohexane 17 hours 96.60%

Technical advances

-The present disclosure provides simple and economic process for preparing anilofos and its analogues.
-Product obtained from the process of the present disclosure has yielded more than 90%.
-Product obtained from the process of the present disclosure has purity more than 95%.
-The present disclosure provides a stable process for preparing an anilofos and its analogues.

The exemplary embodiments herein quantify the benefits arising out of this disclosure and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the 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 will 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.

Any discussion of documents, acts, materials, devices, articles and 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.

While considerable emphasis has been placed herein on the particular features of this disclosure, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other modifications in the nature of the disclosure or the preferred embodiments 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 preparing a compound of Formula 1,

wherein,
X is selected from the group consisting of chlorine, bromine and iodine,
n is an integer in the range of 1 to 2,
R is selected from the group consisting of hydrogen and branched or un-branched C1-C10 alkyl groups, and
R3 is selected from the group consisting of linear or branched C1-C5 alkyl groups,
said process comprising the following steps:
i. amidizing a compound of Formula 2, by reacting said compound of Formula 2 and a compound of Formula 3 to obtain a compound of Formula 4;

wherein,
X, X1 and X2 are independently selected from the group consisting of chlorine, bromine and iodine;
n is an integer in the range of 1 to 2; and
R is selected from the group consisting of hydrogen and branched or un-branched C1-C10 alkyl groups,
ii. alkoxylating phosphorous pentasulfide (P2S5) by reacting phosphorous pentasulfide and a compound of Formula 5 in the presence of at least one first reaction medium to obtain a compound of Formula 6;

wherein, R3 is selected from the group consisting of linear or branched C1-C5 alkyl groups,

iii. basifying the compound of Formula 6 by adding at least one base to obtain a compound of Formula 7; and

wherein, R3 is selected from the group consisting of linear or branched C1-C5 alkyl groups, and
B+ is a cationic part of the base,
iv. condensing the compound of Formula 7 and the compound of Formula 4 in the presence of at least one second reaction medium to obtain a compound of Formula 1.

2. The process as claimed in claim 1 wherein the compound of Formula 1 is represented by

wherein,
X is chlorine,
n is an integer 1,
R is selected from the group consisting of hydrogen and branched or un-branched C1-C3 alkyl groups, and
R3 is selected from the group consisting of linear or branched C1-C3 alkyl groups,
and said process comprising the following steps:
i. amidizing a compound of Formula 2, by reacting said compound of Formula 2 and a compound of Formula 3 to obtain a compound of Formula 4;

wherein,
X, X1 and X2 are chlorine,
n is an integer, and
R is selected from the group consisting of hydrogen and branched or un-branched C1-C3 alkyl groups,
ii. alkoxylating phosphorous pentasulfide (P2S5) by reacting phosphorous pentasulfide and a compound of Formula 5 in the presence of at least one first reaction medium to obtain a compound of Formula 6;

wherein, R3 is selected from the group consisting of linear or branched C1-C3 alkyl groups,

iii. basifying the compound of Formula 6 by adding a base selected from the group consisting of sodium hydroxide and ammonium hydroxide to obtain a compound of Formula 7; and

wherein, R3 is selected from the group consisting of linear or branched C1-C3 alkyl groups, and
B+ is selected from the group consisting of Na+ and NH4+,

iv. condensing the compound of Formula 7 and the compound of Formula 4 in the presence of at least one second reaction medium to obtain a compound of Formula 1.

3. The process as claimed in claim 1, wherein the step of amidizing is carried out at a temperature ranging from 30 to 80 oC.

4. The process as claimed in claim 1, wherein the step of alkoxylating is carried out at a temperature ranging from 10 to 50 oC.

5. The process as claimed in claim 1, wherein the base is selected from the group consisting of ammonia, ammonium hydroxide, sodium hydroxide and potassium hydroxide; the cation B+ is selected from the group consisting of NH4+, Na+ and K+; and the base is in the form of an aqueous solution.

6. The process as claimed in claim 1, wherein the compound of Formula 1 is anilofos, the compound of Formula 2 is 4-chloroisopropyl aniline (IPPCA), the compound of Formula 3 is chloroacetyl chloride, the compound of Formula 4 is 2-chloro-N-(4-chlorophenyl)-N-isopropylacetamide, the compound of Formula 5 is methanol, the compound of Formula 6 is dimethoxy thiophosphric acid (DMTA) and the compound of Formula 7 is sodium salt of dimethoxy thiophosphric acid (DMTA).

7. The process as claimed in claim 1, wherein the first reaction medium and the second reaction medium are independently selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, dimethylformamide (DMF), acetone, acetonitrile, dimethyl sulfoxide (DMSO), ethanol, methanol, xylene, benzene, ethylbenzene, hexane, cyclohexane, toluene and mixtures thereof.

8. The process as claimed in claim 1, wherein the molar ratio of the compound of Formula 2 to the compound of Formula 3 ranges from 1:1 to 1:1.2.

9. The process as claimed in claim 1, wherein the molar ratio of P2S5 and the compound of Formula 5 ranges from 1: 4 to 1: 6.

10. The process as claimed in claim 1, wherein the molar ratio of the compound of Formula 4 to the compound of Formula 7 ranges from 1:1 to 1:1.5.
11. The process as claimed in claim 1, wherein the yield of the compound of Formula 1 is at least 90% and the purity is greater than 96%.