DESC:
FIELD OF THE INVENTION
[0001] The present disclosure generally relatesto the technical field of preparation of esters of substituted phenoxyacetic acid(s). In particular, the presentdisclosure pertains to aprocess for preparation of esters of2,4-dichlorophenoxyacetic acid, specially 2-ethylhexyl 2,4-dichlorophenoxy acetate.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Substituted phenoxyacetic acid derivatives, more particularly estersof 2,4-dichlorophenoxy acetic acid are one of the oldest and most widely available herbicides in the world.2,4-Dichlorophenoxy acetic acid(commonly known as 2,4-D) or its esters or saltsare well known in the art and are primarily used as selective herbicide, which kills many terrestrial and aquatic broadleaf weeds. It acts by mimicking the action of plant growth hormone auxin, which results in uncontrolled growth and eventually death in susceptible plants.2,4-Dichlorophenoxy acetic acid can be found in numerous commercial lawn herbicide mixtures or compositions, and is widely used as a weed-killer on cereal crops, pastures and orchards.
[0004] A person skilled in the art would appreciate that a lot of research work has been done across the globe by different scientists in search forsuitable process for manufacture of substituted phenoxyacetic acid derivatives.
[0005] Patent documents GB1246326, CA733997, SU172301, JP31010777, IT615879, DE1144288, US2769833 and GB573476; research articlesJ.Am.Chem.Soc., 69,718-23(1947); J.Org.Chem.,12,426-33(1947) and PrzemyslChemiczny,(1965),44(6),325-7disclose traditional commercial processes for preparation of esters of phenoxyacetic acids by esterification of the corresponding acids with alcohol, optionally in presence of a catalyst.
[0006] Further, patent documents US4326882, EP178189, JP03218336, WO2008104524, WO1996032399, WO1998003464, WO2000003975, WO2000049007, EP1013639, US20030158435 and WO2004094386; research articlesJ. Ind. Chem. Soc., 79(12),964-965(2002); Molecules,18(2),14876(2013); Eu. J. Med. Chem., 69, 244-61(2013) and J. Het. Chem. 21(5), 1431-5(1984) disclose preparation of esters of phenoxyacetic acids by reacting alkylhaloacetateand substituted phenols. However, in all of thesedocuments, alkyl group in alkylhaloacetate hasmaximum 4 carbon atoms. Further, none of thesedocuments disclose reaction of alkylhaloacetatewithsubstituted phenols, wherein alkyl group in alkylhaloacetatehas more than 4 carbon atoms.
[0007] Preparation of alkylhaloacetate with different number of carbon atoms in alkyl group is known in the art.Patent documents RO122852, CN1058393, CN1435416 and CN102267930 disclose preparation of 2-ethylhexyl chloroacetate by reacting chloroacetic acid and 2-ethylhexanol.
[0008] However, existing methods for preparation of esters of substituted phenoxyacetic acidsuse large quantity of water, base and acid in the reaction,work-up and isolation, which results in unwanted by-products and excessive load on effluent treatment at commercial scale. Many of these processes also suffer from poor selectivity.
[0009] In all of these documents for preparing esters of substituted phenoxyacetic acids as known to the applicant, at least one disadvantage exists. The known route of synthesis are invariably unsatisfactory at large scale because they have drawbacks of their own, including but not limited to, excessive use of water in reaction and work-up;large quantity of unwanted by-products;multiple operational steps;handling and storage of effluent;problems of disposal of waste; andenvironmentally non-friendly.
[00010] Accordingly, there exists a need in the art to develop a suitable process, closer to green chemistry at commercial scale.The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
[00011] Furthermore, the present inventors have intensively studied based on above mentioned findings and tried to complete the present invention closer to green chemistry.

OBJECTS OF THE INVENTION
[00012] Primary object of the present invention is to provide a novel and commercially feasible process for manufacture of esters of substituted phenoxyacetic acids.
[00013] Another object of the present disclosure is to develop a process which is closer to green chemistry.
[00014] Another object of the present invention is to use minimal or no water against the conventional process, which requires 10-30 times of water at commercial scale.
[00015] Another object of the present invention is to provide a process for preparing esters of substituted phenoxyacetic acids, which is simple, safe, time saving, having convenient and lesser operational steps at commercial scale and environment friendly.
[00016] A further object of the present invention is to provide a process for preparing esters of substituted phenoxyacetic acids that abides green chemistry synthesis.
[00017] Yet another object of the present invention is to provide a process for preparing esters of substituted phenoxyacetic acids in mild reaction condition without any adverse effect on yield, purity & stability of final compound.
[00018] Yet another object of the present invention is to provide a process for preparing esters of substituted phenoxyacetic acids which do not corrode the equipment used.
[00019] Other objects and advantages of the present invention will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

SUMMARY OF THE INVENTION
[00020] The present disclosure generally pertains to the technical field of preparation of esters of substituted phenoxyacetic acid(s). In particular, the present disclosure pertains to a process for preparation of esters of 2,4-dichlorophenoxyacetic acid, specially 2-ethylhexyl 2,4-dichlorophenoxy acetate.
[00021] Aspects of the present disclosure relate to a process for preparation of esters of substituted phenoxyacetic acids, represented by Formula (A), including the steps of:esterification of haloacetic acid using an alcohol to form an alkylhaloacetate; and condensation of the alkylhaloacetatewith substituted aryl alcohol, represented by Formula (IV), in a medium comprising at least one solvent, at least one base and optionally at least onecatalyst, wherein R’ is H, Cl or Br and R is aliphatic linear or branched alkyl group containing carbon atoms ranging from C5 to C10.

[00022] In one aspect of the present invention, the alcohol is selected from any or a combination of aliphatic linear or branched alcohol having carbon atoms ranging from C5 to C10.
[00023] In one aspect of the present invention, the solvent is any suitable polar or non-polar solvent,including but not limited to, hydrocarbon solvents such as aliphatic and aromatic; oxygenated solvents such as alcohols, ketones, aldehydes, glycol ethers, esters and glycol ether esters; and halogenated solvents such as chlorinated and brominated hydrocarbons, acetonitrile, dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane and mixture(s) thereof.
[00024] In another aspect of the present invention, the basecan be any or a combination of carbonate, bicarbonate, hydroxide, hydride, alkoxide of alkali or alkaline earth metal, alumina, neutral alumina, lime or organic base like dimethylamine, diethylamine, trimethylamine, triethylamine, pyridine and1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), but not limited thereto.
[00025] In another aspect of the present invention, the catalyst can be any or a combination of sodium iodide, potassium iodide, crown ethers andquaternary ammonium halides, but not limited thereto.
[00026] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION
[00027] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00028] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00029] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00030] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00031] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, process conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00032] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00033] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00034] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00035] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00036] The terminology or phrases described herein are well known and disclosed in the prior art.
[00037] The term “green chemistry” as used herein refers to utilization of a set of principles that reduces or eliminates use or generation of hazardous substance(s) in the design, manufacture and application of chemical products" with 12 principles namely, 1) prevention of large aqueous effluent, 2) atom economy, 3) less hazardous chemical synthesis, 4) safer chemicals, 5) safer solvents and auxiliaries, 6) energy efficiency, 7) lesser amount of by-products, 8) derivatives reduction, 9) catalysis, 10) design for degradation, 11) real-time analysis for pollution prevention, and 12) inherently safer for accident prevention.
[00038] The present disclosure generally pertains to the technical field of preparation of esters of substituted phenoxyacetic acid(s). In particular, the present disclosure pertains to a process for preparation of esters of 2,4-dichlorophenoxyacetic acid, specially 2-ethylhexyl 2,4-dichlorophenoxy acetate.
[00039] Aspects of the present disclosure relate to a process for preparation of esters of substituted phenoxyacetic acids, represented by Formula (A), including the steps of: esterification of haloacetic acid using an alcohol to form an alkylhaloacetate; and condensation of the alkylhaloacetate with substituted aryl alcohol, represented by Formula (IV), in a medium comprising at least one solvent, at least one base and optionally at least one catalyst, wherein R’ is H, Cl or Br and R is aliphatic linear or branched alkyl group containing carbon atoms ranging from C5 to C10.

[00040] In one aspect of the present invention, the alcohol is selected from any or a combination of aliphatic linear or branched alcohol having carbon atoms ranging from C5 to C10.
[00041] In one aspect of the present invention, the solvent is any suitable polar or non-polar solvent,including but not limited to, hydrocarbon solvents such as aliphatic and aromatic; oxygenated solvents such as alcohols, ketones, aldehydes, glycol ethers, esters and glycol ether esters; and halogenated solvents such as chlorinated and brominated hydrocarbons, acetonitrile, dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane and mixture(s) thereof.
[00042] In another aspect of the present invention, the base can be any or a combination of carbonate, bicarbonate, hydroxide, hydride, alkoxide of alkali or alkaline earth metal, alumina, neutral alumina, lime or organic base like dimethylamine, diethylamine, trimethylamine, triethylamine, pyridine and1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), but not limited thereto.
[00043] In another aspect of the present invention, the catalyst can be any or a combination of sodium iodide, potassium iodide, crown ethers andquaternary ammonium halides, but not limited thereto.
[00044] In one embodiment of the present invention, there is provided a novel process for the synthesis of compound of Formula (A) by condensation of compound of Formula (III) with compound of Formula (IV) comprising the following steps:
a) adding compound of Formula (I) in a reactor;
b) adding compound of Formula (II);
c) adding acid to the mixture;
d) raise the temperature and reflux the reaction mixture;
e) stirring the reaction mass and monitoring completion of reaction;
f) cool the mass and separate the layers;
g) distill out to get the intermediate compound of Formula (III);
h) transfer the intermediate compound of Formula (III) in another reactor;
i) adding compound of Formula(IV) and a solvent;
j) optionally adding a base;
k) optionally adding a catalyst;
l) raise the temperature and reflux the reaction mixture;
m) stirring the reaction mass and monitoring completion of reaction;
n) isolate the compound of Formula (A).
[00045] In one embodiment of the present invention, the schematic representation of the reaction is shown in Scheme – 1, wherein X represents Cl, Br or I; R’ represents H, Cl or Br; and R represents linear or branched alkyl group containing carbon atoms ranging from C5 to C10.

[00046] In one embodiment of the present invention, the compound of Formula (I),used in step (a)is X-CH2COOH, wherein X is Cl, Br or I; such as monochloroacetic acid, monobromoacetic acid,monoiodoacetic acid and mixture(s) thereof.
[00047] In one embodiment of the present invention, the compound of Formula (II), used in step (b) is R-OH, whereinR is linear or branched alkyl group containing carbon atoms ranging from C5 to C10.
[00048] In one embodiment of the present invention, the acid used in step (c) is selected from the group consisting of sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, super acids, phosphoric acid and mixture(s) thereof.
[00049] In another embodiment of the present invention, the temperature in step (d) is a suitable reflux temperature.
[00050] In another embodiment of the present invention, the temperature after cooling in step (f) is in the range of 10°C to 35°C, more preferably in the range of 25°C to 30 °C.
[00051] In one embodiment of the present invention, the compound of Formula (III) obtained as an intermediate in step (g) is X-CH2COOR, wherein X is Cl, Br or I and whereinR is linear or branched alkyl group containing carbon atoms ranging from C5 to C10.
[00052] In one embodiment of the present invention, the compound of Formula (IV) used in step (i) is the same as shown in scheme-1, wherein R’ is H, Cl or Br such as phenol, 2,4-dichlorophenol, 2,4,5-trichlorophenol, 2,4-dibromophenol and the like or mixture(s) thereof.
[00053] In one embodiment of the present invention, the solvent used in step (i) is any suitable polar or non-polar solvent selected from the group consisting of hydrocarbon solvents such as aliphatic and aromatic; oxygenated solvents such as alcohols, ketones, aldehydes, glycol ethers, esters and glycol ether esters; and halogenated solvents such as chlorinated and brominated hydrocarbons, acetonitrile, dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane and mixture(s) thereof.
[00054] In one embodiment of the present invention, the base used in step (j) is selected from the group consisting of carbonate, bicarbonate, hydroxide, hydride, alkoxide of alkali or alkaline earth metal salt, alumina, neutral alumina, lime or organic base like dimethylamine, diethylamine, trimethylamine, triethylamine, pyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)and mixture(s) thereof.
[00055] In one embodiment of the present invention, the catalyst used in step (k) is selected from the group consisting of sodium iodide, potassium iodide, crown ethers, quaternary ammonium halidesand mixture(s) thereof.
[00056] In another embodiment of the present invention, the temperature in step (l) is a suitable reflux temperature.
[00057] According to another embodiment of the present invention, pH of a reaction mixture at step (m) is in the range of 8 to 11.
[00058] In another embodiment of the present invention, molar ratio of compound of Formula (I) to the compound of Formula (II) ranges from 1: 5to 5: 1, more preferably 1: 1.2.
[00059] In yet another embodiment of the present invention, molar ratio of compound of Formula (III) to the compound of Formula (IV) ranges from 1: 5 to 5: 1, more preferably 1.1: 1.
[00060] In another embodiment of the present invention, sequence of adding the compound of Formula (I), (II), (III) or (IV), the solvent, the acid, the base and the catalyst as mentioned in steps (a) to (k) can be interchanged according to the suitability of the reaction conditions.
[00061] In yet another embodiment of the present invention, there is use of minimal or no water in step (h) to step (l) against the conventional process, which requires 10-30 times of water at commercial scale.
[00062] In accordance with the present invention, compound of Formula (A) can be obtained in a yield of more than 95%, more preferably more than 97%, with respect to the starting amount of the compound.
[00063] Compound of Formula (A) produced in accordance with the process disclosed herein has a purity of greater than 97%, more preferably a purity of greater than 99.5%. Purity can be determined by HPLC, for example, or other methods known in the art.
[00064] In another embodiment of the present invention, compound of Formula (A) can be converted into corresponding acid derivative by the traditional methods reported in the prior art.

EXAMPLES
[00065] The present invention is further explained in the form of following examples. However it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

EXAMPLE 1: Preparation of 2-Ethylhexyl 2,4-dichlorophenoxyacetate
[00066] To the round bottom flask, fitted with a reflux condenser and stirrer, 47.25g of monochloracetic acid, 78g of 2-Ethylhexanol and 2g of concentrated sulfuric acid was charged. The reaction flask was gently heated to refluxing temperature andstirringwas continued for about 7-8 hours. Reaction was monitored till completion. After reaction completion, the reaction mass was cooled and layers were separated. The 2-ethyl hexyl chloroacetate layer was collected and washed with 50g of 5% sodium bicarbonate solution. After distilling out the excess 2-ethylhexanol,the reaction afforded 102g of 2-ethylhexyl chloroacetate as a colorless liquid (Purity 99.5%; Yield 99%).
[00067] To the round bottom flask, fitted with a reflux condenser and stirrer, 2.47g of 2-ethylhexyl chloroacetate, 1.63g of 2,4-dichlorophenol, 2.76g potassium carbonate and 10g of acetone was charged. The reaction flask was gently heated to refluxing temperatureand stirring was continued for about 6-7 hours. Reaction was monitored till completion on GC. After reaction completion, the reaction mass was distilled out to get 3.2g of the desired compound 2-ethylhexyl 2,4-dichlorophenoxyacetate (Purity 99.6%; Yield 97%).

EXAMPLE 2: Preparation of 2-Ethylhexyl 2,4-dichlorophenoxyacetic acid
[00068] 2-Ethylhexyl 2,4-dichlorophenoxyacetic acid was prepared from 2-ethylhexyl 2,4-dichlorophenoxyacetate (prepared in Example-1) by the conventional methods reported in the literature.
[00069] The numerical values of various parameters given in the specification are at approximations and slightly higher or slightly lower values of these parameters fall within the ambit and the scope of the invention.
[00070] While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be highly appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosures herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

ADVANTAGES
[00071] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that substantially eliminates utilization of water to reduce effluent load at large commercial scale that supports Green Chemistry.
[00072] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that exhibits no sidereactions or unwanted reactions.
[00073] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that exhibits higher degree of effectiveness.
[00074] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that involves effective degree of reaction resulting in competitive high yield of the product with optimum purity at commercial scale.
[00075] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that uses solvents that are recyclable, efficient & environment friendly.
[00076] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids,wherein recovery of HCl generated as by-product is easy, which can be reused.
[00077] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids wherein recovery of catalyst is easy, which can be reused.
[00078] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that is simple, safe, time saving and having convenient operational steps at commercial scale.
[00079] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that utilizes easily available and effective solvents as a substitute for corrosive and expensive solvents.
[00080] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that provides lower impurity profile in final product, as mild reaction condition restricts the formation of undesired impurities.
[00081] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that saves utility at commercial scale because of simple work-up & product isolation procedure.
[00082] The present disclosure provides a process for preparation of esters of substituted phenoxyacetic acids that is safe to people, animals, and the environment.
,CLAIMS:
1. A process for preparing a compound of formula (A),

whereinR is linear or branched alkyl group containing carbon atoms ranging from C5 to C10,and R' is H, Cl or Br,
comprising the steps of:
combining a compound of formula (III)

wherein X is Cl, Br or I, and R is as defined above,
with a compound of formula (IV) in presence of a solvent to form a reaction mixture;

whereinR' is as defined above,
adding a base to the reaction mixture;
optionally adding a catalyst to the reaction mixture; and
heating the reaction mixture to reflux under stirring to yield the compound of formula (A).

2. The process as claimed in claim 1, wherein the compound of formula (III) and the compound of formula (IV) are combined in presence of a solvent selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones, aldehydes, glycol ethers, esters, glycol ether esters, chlorinated hydrocarbons, brominated hydrocarbons, acetonitrile, dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane, and a mixture thereof.

3. The process as claimed in claim 1, wherein the base is selected from the group consisting of alkali earth metal carbonate, alkaline earth metal carbonate, bicarbonate, hydroxide, hydride, alkoxide, alumina, neutral alumina, lime, dimethylamine, diethylamine, trimethylamine, triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and a mixture thereof.

4. The process as claimed in claim 1, wherein the catalyst is selected from the group consisting of sodium iodide, potassium iodide, crown ethers, quaternary ammonium halides, and a mixture thereof.

5. The process as claimed in claim 1, wherein the heating the reaction mixture to reflux under stirring comprises heating the reaction mixture to reflux under stirring at a pH of 8 to 11.

6. The process as claimed in claim 1, wherein a molar ratio of the compound of formula (III) to the compound of formula (IV) ranges from 1: 5 to 5: 1.

7. The process as claimed in claim 1, wherein a molar ratio of the compound of formula (III) to the compound of formula (IV) is 1.1 : 1.

8. The process as claimed in claim 1, further comprising the step of isolating the compound of formula (A).
9. The process as claimed in claim 1, wherein the process provides the compound of formula (A) at a yield of greater than 95% with respect to the compound of formula (IV).

10. The process as claimed in claim 1, wherein the compound of formula (A) has a purity of greater than 97% as measured by HPLC.

11. A process for preparing a compound of formula (A),

whereinR is linear or branched alkyl group containing carbon atoms ranging from C5 to C10, and R' is H, Cl or Br,
comprising the steps of:
reacting a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (III);

wherein X is Cl, Br or I; and R is as defined above,
combining the compound of formula (III) with a compound of formula (IV) in presence of a solvent to form a reaction mixture;

whereinR' is as defined above,
adding a base to the reaction mixture;
optionally adding a catalyst to the reaction mixture; and
heating the reaction mixture to reflux under stirring to yield the compound of formula (A).