DESC:Field of the Invention:
This invention belongs to the field of pesticide synthesis, and more particularly relates to a one pot two step preparation process of the Haloxyfop-R-methyl ester of formula-1a, which is used as an herbicide.

Formula-1a
Background of the Invention:
Haloxyfop-r-methyl, a heterocyclic oxy group phenoxy propionic acid ester, the lipid synthesis inhibitor, when absorbed by weeds gets transferred into the whole plant body very soon and hydrolyzes into an acid, and suppress the growth of tissues such as roots of plants, stem, leaf, etc., thereby causing its death. It is an important fragrant of phenoxy propionic acid ester a weedicide, having efficient, highly selective, low residue characteristics and is widely used in soybean, cotton, peanut, rape, vegetables crops etc., and also for the control of annual and perennial monocotyledon weeds.
EP0344746A2 patent discloses the process of preparation of Haloxyfop-r-methyl by reacting R-2-(4- hydroxyphenoxy) propionic acid with 2,3-dichloro-5-trifluoromethyl pyridine in-presence of potassium carbonate in dimethyl sulfoxide followed by reaction with methyl iodide. The said process has following disadvantages includes usage of costly reagent methyl iodide for esterification. Moreover, in the workup process includes the usage of perchloroethylene. According to U.S. Environmental Protection Agency (EPA) toxicological review “perchloroethylene likely to be carcinogenic to humans”. By considering all the above disadvantages, the above said process is not suitable on commercial scale production.
Further the prior art references disclose several methods to prepare this inventive compound, but in multiple steps that require either waste disposal and/or recycling which often results in elaborate or expensive apparatus and includes high energy expenditures. So, there is still a need for new methods that are less costly, efficient, and flexible, eco-friendly process which is more convenient to operate with minimum effluent generation. Thus, there is a need for a process like the present inventive process for producing the desired product, which is simple in operation, eco-friendly and cost-effective process for industrial production.
Summary of the Invention
The first embodiment of the present invention provides a process for the preparation of Haloxyfop-R-Methyl of formula-1a.
The second embodiment of the present invention provides a process for the preparation of Haloxyfop-R-Methyl of formula-1a.
Detailed Description of the Invention
For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The system, methods, and examples provided herein are only illustrative and not intended to be limiting.
In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.
The term "solvent" used in the present invention refers to "non-polar solvents like “hydrocarbon solvents" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term "acid" used in the present invention selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, methane sulfonic acid, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, and thereof. The term “agrochemical acceptable salts” or “salts” described in hereinbefore are obtained by reacting compound with acid selected from the above description.
The term "base" used in the present invention selected from but not limited to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, trimethylamine, triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide mixtures thereof.
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
The present inventive process provides a simple synthetic method with less overall reaction time for the industrial preparation of haloxyfop-r-methyl ester. In this process, we are able to make the Haloxyfop-R-methyl ester, in one-pot two-step process (without isolation of intermediate), having several advantages for industrial manufacturing.
The present inventive chemical process describs, the one pot two-step synthesis of Haloxyfop-R-Methyl at industrial scale with high yields and quality from the commercially available starting materials, such as (R)-2-(4-hydroxyphenoxy) propionic acid and 2,3-dichloro-5-trifluoromethylpyridine (or) 2-fluoro-3-chloro-5-trifluoromethylpyridine as follows:

Here, (R)-2-(4-hydroxyphenoxy) propionic acid reacts with 2,3-dichloro-5-trifluoro methylpyridine (or) 2-fluoro-3-chloro-5-trifluoromethylpyridine, in DMF or DMAc as a solvent, in presence of inorganic base and methylating reagent (dimethyl sulfate).
The first embodiment of the present invention provides a process for the preparation of Haloxyfop-R-Methyl of formula-1a, comprising: reacting (R)-2-(4-hydroxyphenoxy) propionic acid with 2,3-dichloro-5-trifluoro methylpyridine in presence of inorganic base in a solvent followed by in-situ with methylating reagent to provide Haloxyfop-R-Methyl of formula-1a

In the first aspect of first the embodiment, solvent is selected from but not limited to polar aprotic solvent, preferably DMF or DMAc; inorganic base is selected from but not limited to metal carbonate or metal bicarbonate, preferably potassium carbonate.
In the second aspect of first the embodiment methylating reagent is selected from dimethyl sulfate.
The second embodiment of the present invention provides a process for the preparation of Haloxyfop-R-Methyl of formula-1a, comprising: reacting (R)-2-(4-hydroxyphenoxy) propionic acid with 2-fluoro-3-chloro-5-trifluoromethylpyridine in presence of inorganic base in a solvent followed by in-situ with methylating reagent to provide Haloxyfop-R-Methyl of formula-1a.

In the first aspect of second the embodiment, solvent is selected from but not limited to polar aprotic solvent, preferably DMF or DMAc; inorganic base is selected from but not limited to metal carbonate or metal bicarbonate, preferably potassium carbonate.
In the second aspect of second the embodiment methylating reagent is selected from dimethyl sulfate.

The novel features and advantages of this one-pot inventive process are as follows:
1. It reduces or avoids the operations (like work up, filtrations and drying of solids, in each stage) in commercial scale, which will have impact on time cycle, energy, and manpower consumption.
2. Avoids the usage of additional reagent or solvent.
3. Reduction of chemical effluents or reduces the generation of chemical effluents will have high impact on environment protection and helps in handing the reaction on commercial scale.
4. Methylation is performed with cheaper dimethyl sulfate as a reagent, instead of expensive Methyl iodide, which will have economic effect in commercial scale (cost effective process).
Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to any of the processes known in the prior art.
The present invention described in embodiments and examples are merely helping to understand the present invention. These examples are for illustrative purposes only and no way limit the scope of the present invention.
Examples:
Example-1: Haloxyfop-R-Methyl of formula-1a
Potassium carbonate (436.6 g, 2.3 mole equivalent) and 2,3-dichloro-5-trifluoromethyl pyridine (299.39 g, 1.01 mole equivalent) were added to the mixture of dimethylformamide (437 ml) and (R)-2-(4-Hydroxyphenoxy)propanoic acid (250 g, 1 mole equivalent) at room temperature. Heated the reaction mixture to 80-85? and stirred the reaction mixture for 4 hours at same temperature. Cooled the mixture to room temperature and dimethyl sulfate (200 g, 1.15 mole equivalent) was added to the above mixture. Stirred the reaction mixture for 4 hours at the same temperature. Distilled off 70% of the solvent from the reaction mixture. Water and ethylene dichloride were added to the above obtained mixture. pH was adjusted to 7.5 to 8.0 by concentrated hydrochloric acid and stirred for 15 minutes. Layers separated. The Aqueous layer was extracted with ethylene dichloride. Combined the layers and washed with Sodium dithionate. Layers separated. Distilled off the solvent completely from organic layer. Cyclohexane and silica gel were added to the above obtained residue and stirred for 30 minutes. Filtered the solid through silica gel bed and washed with cyclohexane. Distilled off the solvent completely from filtrate to get the titled compound.
Yield: 432 g (83.72%), Purity: 98.91% (by HPLC).
Example-1: Haloxyfop-R-Methyl of formula-1a
Potassium carbonate (436.6 g, 2.3 mole equivalent) and 2,3-dichloro-5-trifluoromethyl pyridine (299.39 g, 1.01 mole equivalent) were added to the mixture of dimethylformamide (437 ml) and (R)-2-(4-Hydroxyphenoxy)propanoic acid (250 g, 1 mole equivalent) at room temperature. Heated the reaction mixture to 80-85? and stirred the reaction mixture for 4 hours at same temperature. Cooled the mixture to room temperature and dimethyl sulfate (200 g, 1.15 mole equivalent) was added to the above mixture. Stirred the reaction mixture for 4 hours at the same temperature. Distilled off 70% of the solvent from the reaction mixture. Water and ethylene dichloride were added to the above obtained mixture. pH was adjusted to 7.5 to 8.0 by concentrated hydrochloric acid and stirred for 15 minutes. Layers separated. The Aqueous layer was extracted with ethylene dichloride. Combined the layers and washed with Sodium dithionate. Layers separated. Distilled off the solvent completely from organic layer. Cyclohexane and silica gel were added to the above obtained residue and stirred for 30 minutes. Filtered the solid through silica gel bed and washed with cyclohexane. Distilled off the solvent completely from filtrate to get the titled compound.
Yield: 432 g (83.72%), Purity: 98.91% (by HPLC).

Example-2: Haloxyfop-R-Methyl of formula-1a
Potassium carbonate (436.6 g, 2.3 mole equivalent) and 2-fluro-3-chloro-5-trifluoromethyl pyridine (280 g, 1.02 mole equivalent) were added to the mixture of dimethylformamide (437 ml) and (R)-2-(4-Hydroxyphenoxy)propanoic acid (250 g, 1 mole equivalent) at room temperature. Heated the reaction mixture to 80-85? and stirred the reaction mixture for 4 hours at same temperature. Cooled the mixture to room temperature and dimethyl sulfate (200 g, 1.15 mole equivalent) was added to the above mixture. Stirred the reaction mixture for 4 hours at the same temperature. Distilled off 70% of the solvent from the reaction mixture. Water and ethylene dichloride were added to the above obtained mixture. pH was adjusted to 7.5 to 8.0 by concentrated hydrochloric acid and stirred for 15 minutes. Layers separated. The Aqueous layer was extracted with ethylene dichloride. Combined the layers and washed with Sodium dithionate. Layers separated. Distilled off the solvent completely from organic layer. Cyclohexane and silica gel were added to the above obtained residue and stirred for 30 minutes. Filtered the solid through silica gel bed and washed with cyclohexane. Distilled off the solvent completely from filtrate to get the titled compound.
Yield: 419.40 g (81.28%), Purity: 98.34% (by HPLC).
,CLAIMS:We Claim:
1. A process for the preparation of Haloxyfop-R-Methyl of formula-1a, comprising:
reacting (R)-2-(4-hydroxyphenoxy) propionic acid with 2,3-dichloro-5-trifluoro methylpyridine in presence of inorganic base in a solvent followed by in-situ reaction with methylating reagent to provide Haloxyfop-R-Methyl of formula-1a.

2. The process as claimed in claim 1, the solvent is selected from but not limited to polar aprotic solvent; inorganic base is selected from but not limited to metal carbonate or metal bicarbonate.
3. The process as claimed in claim 2, wherein the polar aprotic solvent is DMF or DMAc.
4. The process as claimed in claim 2, wherein the metal carbonate is potassium carbonate.
5. The process as claimed in claim 1, methylating reagent is dimethyl sulfate.
6. A process for the preparation of Haloxyfop-R-Methyl of formula-1a, comprising:
reacting (R)-2-(4-hydroxyphenoxy) propionic acid with 2-fluoro-3-chloro-5-trifluoromethylpyridine in presence of inorganic base in a solvent followed by in-situ reaction with methylating reagent to provide Haloxyfop-R-Methyl of formula-1a.

7. The process as claimed in claim 6, the solvent is selected from but not limited to polar aprotic solvent; and inorganic base is selected from but not limited to metal carbonate or metal bicarbonate.
8. The process as claimed in claim 7, wherein the polar aprotic solvent is DMF or DMAc.
9. The process as claimed in claim 7, wherein the metal carbonate is potassium carbonate.
10. The process as claimed in claim 6, methylating reagent is dimethyl sulfate.