DESC:Field of invention
The present invention relates to a process for preparation of fungicidally active carboxamide compounds and intermediates thereof.

Background of the disclosure
Fungicidally active carboxamides such as Boscalid, Bixafen and Fluxapyroxad are highly efficacious fungicides.

Boscalid, having chemical name 2-chloro-N-(4'-chlorobiphenyl-2-yl)pyridine-3-carboxamide was first disclosed in US5589493. Bixafen, having chemical name N-(3',4'-Dichloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide was first disclosed in US7329633. Fluxapyroxad, having chemical name 3-(Difluoromethyl)-1-methyl-N-(3',4',5'-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide was first disclosed in US8008232.

Most of the processes for preparation of fungicidally active carboxamides having formula (I)

wherein, A is a selected from group comprising of (A1) or (A2)

X1and X2 are independently selected from hydrogen or halogen; n is 0, 1, 2 or 3; and m is 0, 1 or 2; proceeds through preparation of aminobiphenyl compounds of formula (IV), followed by coupling of said aminobiphenyl compounds of formula (IV) with pyrazole or pyridine compound of formula (Va) or (Vb).

wherein, X1, X2, m and n are same as defined above; Y is hydrogen or protecting group and Q is selected from carboxylic acid group or derivatives thereof.

Different processes known in the art involve two steps for the preparation of aminobiphenyl compounds of formula (IV) and coupling of aminobiphenyl compounds of formula (IV) with pyrazole or pyridine compound of formula (Va) or (Vb) are carried out separately wherein different solvents are used. Furthermore, each step requires isolation of intermediate compounds and purification of the intermediate thereby increasing number of operations and cost of overall process.

The inventors of present invention have developed an economical and eco-friendly process for preparation of carboxamide compound of formula (I), to overcome the drawback of the above processes without adversely affecting the yield and purity of desired carboxamide compounds.

OBJECTIVE OF THE INVENTION
It is an objective of the present invention to provide carboxamide compounds of formula (I) or salts thereof in high yield and purity.

It is an objective of the present invention to provide a process for the preparation of carboxamide compounds of formula (I) or salts thereof.

It is another objective of the present invention to provide a process for the preparation of carboxamide of compounds formula (I) or salts thereof using a single solvent.

It is an objective of the present invention to provide an economic and eco-friendly process for the preparation of carboxamide compounds of formula (I) or salts thereof.

SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided a process for preparation of carboxamide compounds of formula (I) or salts thereof,

wherein, A is a selected from the group comprising of (A1) or (A2)

X1and X2 are independently selected from hydrogen or halogen; n is 0, 1, 2 or 3; and m is 0, 1 or 2
comprising the steps of
i) reacting a boronic acid of formula (II) with a compound of formula (III) in presence of a palladium catalyst to obtain compound of formula (IV)

wherein Y is a selected from hydrogen or a protecting group; and X1, X2, n and m are same as defined above;
ii) reacting a compound of formula (IV) with a compound of formula (Va) or (Vb) to obtain the carboxamide compound of formula (I);

wherein Q is selected from carboxylic acid group or derivatives thereof;
wherein each step of the process is carried out in an alcoholic solvent.
According to an aspect of the present invention, there is provided a process for preparation of Fluxapyroxad of formula (Ia) or salts thereof,

comprising steps of
i) reacting a boronic acid of formula (IIa) with a compound of formula (IIIa) in presence of a palladium catalyst to obtain a compound of formula (IVa)

wherein X2 is selected from halogen;
ii) reacting the compound of formula (IVa) with a compound of formula (Va) to obtain Fluxapyroxad of formula (Ia);

wherein Q is selected from carboxylic acid group or derivative thereof;
wherein each step of the process is carried out in an alcoholic solvent.
According to an aspect of the present invention, there is provided a process for preparation of Bixafen of formula (Ib) or salts thereof,

comprising steps of
i) reacting a boronic acid of formula (IIb) with a compound of formula (IIIb) in presence of a palladium catalyst to obtain a compound of formula (IVb)

ii) reacting the compound of formula (IVb) with a compound of formula (Va) to obtain Bixafen of formula (Ib);

wherein Q is selected from carboxylic acid group or a derivative thereof
wherein each step of the process is carried out in an alcoholic solvent.
According to an aspect of the present invention, there is provided a process for preparation of Boscalid of formula (Ic) or salts thereof,

comprising steps of
i) reacting a boronic acid of formula (IIc) with a compound of formula (IIIa) in presence of a palladium catalyst to obtain a compound of formula (IVc)

wherein X2 is selected from halogen;
ii) reacting the compound of formula (IVc) with a compound of formula (Vb) to obtain Boscalid of formula (Ic);

wherein Q is selected from carboxylic acid group or a derivative thereof;

wherein each step of the process is carried out in an alcoholic solvent.

In an embodiment, the purity of the carboxamide compounds obtained by the process of the present invention is greater than 90%, preferably greater than 95%.

DETAILED DESCRIPTION OF THE INVENTION
The following description is provided to assist in a comprehensive understanding of exemplary embodiments of the disclosure. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the disclosure. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness. The terms used in the following description and claims are not limited to the bibliographical meanings but are merely used by the inventor to enable a clear and consistent understanding of the disclosure. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present disclosure are provided for illustration purpose only and not for limiting the scope of the disclosure as defined by the appended claims and their equivalents.

For the purposes of the present disclosure, it is to be understood that the disclosure may assume various alternative variations and step sequences, except where expressly specified to the contrary. Moreover, other than in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of materials/ingredients used in the specification are to be understood as being modified in all instances by the term “about”. Thus, before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particularly exemplified systems or process parameters that may of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the disclosure only and is not intended to limit the scope of the disclosure in any manner. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the disclosure or of any exemplified term. Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms used herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, suitable methods and materials are described herein.

As used herein, the terms “comprising”, “including”, “having”, “containing”, “involving” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. The terms “preferred” and “preferably” refer to embodiments of the disclosure that may afford certain benefits, under certain circumstances. The aspects and embodiments described herein shall also be interpreted to replace the clause “comprising” with either “consisting of” or with “consisting essentially of” or with “consisting substantially of”.

“About” or “approximately” as used herein is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ±10% or ±5% of the stated value.
The use of the terms “a”, “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc., as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers.
All methods described herein can be performed in a 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”), is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure as used herein.
While the disclosure has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made, and equivalents may be substituted for elements thereof without departing from the scope of the disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from the essential scope thereof. Therefore, it is intended that the disclosure is not limited to the particular embodiment disclosed as the best mode contemplated for carrying out this disclosure, but that the disclosure will include all embodiments falling within the scope of the appended claims.
As used herein, the term “halogen” refers to chlorine, fluorine, bromine or iodine.
As used herein, the term “carboxylic acid or derivatives thereof” refers to the group -COOH or its derivatives such as acid halide group -C(O)X; wherein X is halogen selected from bromine, chlorine, fluorine and iodine.
As used herein, the term “acyl” refers to the group RaC(O)-, where Ra is C1 to C6 alkyl group.
As used herein the (C1-C6) alkyl means a linear or branched chain alkyl having 1 to 6 carbon atoms. Examples of (C1-C6) alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and the like.
The term “carboxamide compound of formula (I)” is used interchangeably with the term “carboxamide of formula (I) or salts thereof”.
The term “Fluxapyroxad of formula (Ia)” is used interchangeably with the term “Fluxapyroxad of formula (Ia) or salts thereof”.
The term “Bixafen of formula (Ib)” is used interchangeably with the term “Bixafen of formula (Ib) or salts thereof”.
The term “Boscalid of formula (Ic)” is used interchangeably with the term “Boscalid of formula (Ic) or salts thereof”.
A salt can form from a compound in any manner familiar to the skilled artisan. Accordingly, the recitation "to form a compound or salt thereof includes embodiments where a compound is formed and the salt is subsequently formed from the compound in a manner familiar to the skilled artisan.
The term “in-situ” refers to process wherein all operations or procedures that are performed in place without requiring isolation/purification of intermediate formed in the process.
As used herein, the term “alcoholic solvent” refers to solvent system comprising at least one alcohol.
According to an aspect of the present invention, there is provided a process for preparation of carboxamide compound of formula (I) or salts thereof,

wherein, A is a selected from group comprising of (A1) or (A2)

X1and X2 are independently selected from hydrogen or halogen; n is 0, 1, 2 or 3; and m is 0, 1 or 2
comprising steps of
i) reacting a boronic acid of formula (II) with a compound of formula (III) in presence of a palladium catalyst to obtain a compound of formula (IV)

wherein Y is a selected from hydrogen or a protecting group; and X1, X2, n and m are same as defined above;
ii) reacting the compound of formula (IV) with a compound of formula (Va) or (Vb) to obtain carboxamide compound of formula (I);

wherein Q is selected from carboxylic acid group or derivatives thereof;
wherein each step of the process is carried out in an alcoholic solvent.
In an embodiment, the carboxamide compound of formula (I) is selected from Fluxapyroxad of formula (Ia), Bixafen of formula (Ib) or Boscalid of formula (Ic)

In an embodiment, the boronic acid compound of formula (II) is selected from compound of formula (IIa), (IIb) or (IIc).

The chemical name of compound of formula (IIa) is 3,4,5-trifluorophenyl)boronic acid.
The chemical name of compound of formula (IIb) is 3,4-dichlorophenylboronic acid.
The chemical name of compound of formula (IIc) is 4-chlorophenylboronic acid.
The compound of formula (II) used as starting materials in said process of present invention are prepared by methods known in the art.
In an embodiment, in the compound of formula (III), X2 is independently selected from hydrogen, bromine, chlorine, iodine or fluorine; m is 0, 1, 2, 3 or 4 and Y is a selected from hydrogen or a protecting group.
In an embodiment, in the compound of formula (III), Y is protecting group selected from group comprising of acyl, tosyl, mesyl, carbamate protecting group such as tert-butyloxycarbonyl, ethylcarbamate, benzyloxycarbonyl, benzene sulfonyl, p-nitrobenzene sulfonyl, trifluoro acetyl, tert-butyl sulfonyl, optionally substituted pyrazole acid, optionally substituted nicotinyl acid and the like.
In an embodiment, in the compound of formula (III), wherein m is 1; X2 is bromine or chlorine; and Y is hydrogen.
In an embodiment, the compound of formula (III) is selected from a compound of formula (IIIa) or (IIIb)

wherein X2 and Y has same meaning as above.
In an embodiment, the compound of formula (III) is a compound of formula (IIIa); wherein m is 1; X2 is bromine; and Y is a selected from hydrogen or a protecting group.

In an embodiment, in the compound of formula (IIIa), m is 1; X2 is bromine; and Y is hydrogen.
In an embodiment, in the compound of formula (IIIa) is 2-bromo aniline.
In an embodiment, in the compound of formula (III), m is 2, X2 is independently bromine and fluorine; and Y is a selected from hydrogen or a protecting group.
In an embodiment, the compound of formula (III) is a compound of formula (IIIb); wherein m is 2, X2 is independently bromine and fluorine; Y is a selected from hydrogen or a protecting group.

In an embodiment, in the compound of formula (IIIb), m and X2 are same as defined above; and Y is hydrogen.
In an embodiment, in the compound of formula (IIIb) is 2-bromo, 4-fluoro aniline.The compound of formula (III) used as starting materials in said process of present invention are prepared by methods known in the art.
In an embodiment, the amount of compound of formula (III) used may vary from 0.5 to 1.5 moles with respect to compound of formula (II).
In an embodiment, the amount of compound of formula (III) used may vary from 0.8 to 1.2 moles with respect to compound of formula (II).
In an embodiment, the palladium catalyst is selected from heterogenous catalyst or homogenous catalyst.
In an embodiment, the palladium catalyst used is heterogenous palladium catalyst.
In an embodiment, the heterogenous palladium catalyst is selected from palladium catalyst supported on inert material or inorganic palladium compounds.
In an embodiment, the heterogenous palladium catalyst are supported catalyst such as metallic palladium, organic or inorganic palladium compounds may be used. Suitable organic or inorganic palladium compounds are preferably palladium salts such as acetate or propionate, chloride, hydroxide, bromide, iodide, nitrate, sulfate.
In an embodiment, the heterogenous palladium catalyst used is supported on inert material such as activated carbon, aluminum oxide, barium sulfate, calcium carbonate, pumice, alumina, kieselguhr or silica gel.
In an embodiment, the palladium catalyst is selected from, but not limited to palladium black or palladium on supports, such as palladium on carbon, palladium hydroxide on carbon, palladium on barium sulfate, palladium on calcium carbonate.
In an embodiment, the supported palladium catalyst is palladium on carbon.
In an embodiment, the supported palladium catalyst contains from about 1% to about 30% by weight of palladium, based on the support material.
In an embodiment, the supported palladium catalyst contains from about 2% to about 20% by weight of palladium, based on the support material.
In an embodiment, the supported palladium catalyst contains from about 2% to about 15% by weight of palladium, based on the support material.
In an embodiment, the heterogenous palladium catalyst is used in an amount ranging from about 0.01 mol% to about 10 mol%.
In an embodiment, the palladium catalyst used is homogenous palladium catalyst.
In an embodiment, the homogenous palladium catalyst used is in the form of a complex consisting of palladium in the zero oxidation state and a phosphine ligand.
In an embodiment, the homogenous palladium catalyst used is selected from [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) or bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.
In an embodiment, the homogenous palladium catalyst used is [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).
In an embodiment, the homogenous palladium catalyst used is bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.
The homogenous palladium catalysts used are generally produced in situ from at least one palladium(II) salt or a palladium(0) compound and the corresponding phosphine ligands.
Suitable palladium sources are for example selected from the group consisting of palladium trifluoroacetate, palladium fluoroacetylacetonate, Pd(OAc)2, Pd(OCOCH2CH3)2, Pd(OH)2, PdCl2, PdBr2, Pd(acac)2 (acac=acetylacetonate), Pd(NO3)2, Pd(dba)2, Pd2 dba3 (dba=dibenzylideneacetone), Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Li[PdCl4], Pd/C or palladium nanoparticles.
The molar ratio of palladium to the phosphine ligand is between about 1:1 and about 1:100, preferably between about 1:1 and about 1:5, particularly preferably between 1:1 and 1:2.
When carrying out the reaction, the catalyst system (Palladium source and ligand) can be added together or separately either at room temperature or at an elevated temperature. The system can be prepared separately, immediately before the reaction is carried out, by combining a palladium salt and the ligand, or it can be purchased in crystalline form. Also possible is the direct addition of the ligand and then of the palladium salt to the batch (in situ process).
In the process of the present invention, the homogenous palladium catalyst is used in an amount ranging from about 0.0001 to 5 mol %, based on compound of formula (II).
In an embodiment, the step i) of the process is carried out in presence of a base selected from the group comprising of alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal and alkaline earth metal acetates, alkali metal and alkaline earth metal formates, alkali metal and alkaline earth metal alcoholates, primary, secondary and tertiary amines and mixtures thereof.
In an embodiment, the base used is alkali metal carbonates such as potassium carbonate, sodium carbonate and the likes.
In an embodiment, the amount of base used may vary from about 0.5 to 5 moles with respect to compound of formula (II).
In an embodiment, the step i) of the process is carried out in presence of a phase transfer catalyst.
In an embodiment, the phase transfer catalyst used is selected from the group comprising of, but not limited to, a quaternary ammonium salt, an amine N-oxide compound, a quaternary phosphonium salt, a crown ether compound and a polyethylene glycol compound. The quaternary ammonium salt is preferable.
In an embodiment, the phase transfer catalyst used is the quaternary ammonium salt such as tetraallyl ammonium hydroxide, tetraallyl ammonium halide.
In an embodiment, the phase transfer catalyst used is the quaternary ammonium salt such as benzyltrialkylmmonium hydroxide, tetrabutylammonium hydroxide, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, cetyl trimethyl ammonium chloride, dodecyltrimethylammonium chloride, tetrabutyl ammonium bisulfate, tricaprylylmethylammonium chloride (Aliquat 336) and the like.
In an embodiment, the step i) of the process is carried out at a temperature between 10 and 200°C, preferably between 30 and 150°C.
In an embodiment, the compound of (IV) obtained in step i) is not isolated.
In an embodiment, the compound of (IV) obtained in step i) is isolated.
In an embodiment, the compound of (IV) obtained is represented by formula (IVa), (IVb) or (IVc), wherein Y has same meaning as above

In an embodiment, the compound of formula (Va) wherein Q is carboxyl group is used.
In an embodiment, the compound of formula (Va) is 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid.
In an embodiment, the compound of formula (Va) wherein Q is carbonyl halide group is used.
In an embodiment, the compound of formula (Va) is 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride.
In an embodiment, the compound of formula (Vb) wherein Q is carboxyl group is used.
In an embodiment, the compound of formula (Vb) is 2-chloronicotinic acid.
In an embodiment, the compound of formula (Vb) wherein Q is carbonyl halide group is used.
In an embodiment, the compound of formula (Vb) is 2-chloronicotinoyl chloride.
In an embodiment, the amount of compound of formula (Va) or (Vb) used is in the range of about to 0.1 to about 1.5 with respect to compound of formula (II).
In an embodiment, step ii) of reaction is carried out in presence of an acid scavenger.
In an embodiment, acid scavenger is an organic base. Suitable organic base is selected from the group comprising of N, N-dimethylaniline, trimethylamine, triethylamine, diisopropylethylamine, N-methylpiperidine, pyridine, collidine, lutidine and 4-dimethylaminopyridine, and bicyclic amines.
In an embodiment, the step ii) of the process is carried out at temperature ranging from about 0°C to about 50°C.
In an embodiment, the step ii) of the process is carried out at temperature ranging from about 10°C to 40°C.
In an embodiment, the step i) and ii) of the process of the present invention is carried out in an alcoholic solvent.
In an embodiment, the alcoholic solvent may comprise water.
In an embodiment, the alcoholic solvent used is selected from C3 to C8 alcohols or mixtures thereof.
In an embodiment, the C3 to C8 alcohols is selected from n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol and so on.
In an embodiment, the alcoholic solvent is single solvent selected from C3 to C8 alcohols.
In an embodiment, the alcoholic solvent is n-butanol.
In another embodiment, the alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent.
In another embodiment, the second solvent selected from water; aromatic hydrocarbons; chlorinated hydrocarbons or alcohols.
In another embodiment, the second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In an embodiment, the alcoholic solvent is mixture of first and second solvent independently selected from C3 to C8 alcohols.
In another embodiment, the alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In a preferred embodiment, the alcoholic solvent is mixture of butanol and water.
In an embodiment, the ratio of first solvent to second solvent is in range of about 1:0.1 to about 1:10.
In an embodiment, the ratio of first solvent to second solvent is in range of about 1: 0.1 to 1:5.
In an embodiment, the ratio of first solvent to second solvent is in range of about 1:0.5 to about 1:1.
In an embodiment, the ratio of first solvent to second solvent is about 1:0.8.
In an embodiment, the ratio of first solvent to second solvent is in range of about 1:1 to about 1:5.
In an embodiment, the ratio of first solvent to second solvent is about 1:2.
The present invention provides an in-situ process for preparation of carboxamide carboxamide of formula (I) or salts thereof, utilizing single organic solvent. Said process is accomplished in a single solvent (for example C3- C8 alcohol), without requiring isolation/purification of intermediate of formula (IV) or change of solvent.
In an embodiment, the carboxamide compound of formula (I) is selected from Fluxapyroxad, Bixafen or Boscalid; the boronic acid compound of formula (II) is selected from 3,4,5-trifluorophenyl)boronic acid, 3,4-dichlorophenylboronic acid or 4-chlorophenylboronic acid; the compound of formula (III) is selected from the compound of formula (IIIa) or (IIIb);

the compound of (IV) is selected from the compound of formula (IVa), (IVb) or (IVc);

the compound of formula (Va) is selected from 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid or 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride; the compound of formula (Vb) is selected from 2-chloronicotinic acid or 2-chloronicotinoyl chloride; and wherein X2 and Y has same definition as above.
All combinations of the present embodiments pertaining to the aspects described herein are specifically embraced by the present invention just as if each and every combination was individually explicitly recited, to the extent that such combinations embrace possible aspects. In addition, all sub-combinations of the embodiments contained within the aspects described herein, as well as all sub-combinations of the embodiments contained within all other aspects described herein, are also specifically embraced by the present invention just as if each and every sub-combination of all embodiments are explicitly recited herein. Examples of such embodiments are described hereinafter.
According to an aspect of the present invention, there is provided a process for preparation of Fluxapyroxad of formula (Ia) or salts thereof,

comprising steps of
i) reacting boronic acid of formula (IIa) with a compound of formula (IIIa) in presence of a palladium catalyst to obtain a compound of formula (IVa)

wherein X2 is selected from halogen; Y is hydrogen or protecting group;
ii) reacting the compound of formula (IVa) with a compound of formula (Va) to obtain Fluxapyroxad of formula (Ia);

wherein Q is selected from carboxylic acid group or derivative thereof;
wherein each step of the process is carried out in an alcoholic solvent.
In an embodiment, in the compound of formula (IIIa), X2 is selected from chlorine or bromine; and Y is hydrogen or protecting group.
In an embodiment, the process is carried out in situ without requiring step of isolation and purification of compound of formula (IVa).
In an embodiment, the palladium catalyst used can be heterogenous catalyst or homogenous catalyst.
In an embodiment, the homogenous palladium catalyst used is [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).
In an embodiment, the homogenous palladium catalyst used is bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.
In an embodiment, the compound of formula (Va) wherein Q is carboxylic acid group is used.
In an embodiment, the compound of formula (Va) wherein Q is derivative of carboxylic acid group.
In an embodiment, the compound of formula (Va) is 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride.
In an embodiment, the step i) and ii) of the process of the present invention is carried out in an alcoholic solvent.
The alcoholic solvent comprises of an alcohol selected from C3 to C8 alcohols or its mixture.
In an embodiment, the alcoholic solvent is n-butanol.
In another embodiment, alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent.
In another embodiment, the second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In an embodiment, alcoholic solvent is mixture of first and second solvent independently selected from C3 to C8 alcohols.
In another embodiment, alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In a preferred embodiment, the alcoholic solvent is mixture of butanol and water.
In an embodiment, the alcoholic solvent comprises of mixture of butanol and water.
In an embodiment, the ratio of butanol to water is in range of about 1:0.1 to about 1:10, preferably the ratio of butanol to water is in range of 1:0.1 to 1:5.
According to an aspect of the present invention, there is provided a process for preparation of Bixafen of formula (Ib) or salts thereof,

comprising steps of
i) reacting a boronic acid of formula (IIb) with a compound of formula (IIIb) in presence of a palladium catalyst to obtain a compound of formula (IVb)

wherein X2 is selected from halogen; Y is hydrogen or protecting group;
ii) reacting the compound of formula (IVb) with a compound of formula (Va) to obtain Bixafen of formula (Ib);

wherein Q is selected from carboxylic acid group or derivative thereof;
wherein each step of the process is carried out in an alcoholic solvent.
In an embodiment, the process is carried out in situ without requiring step of isolation and purification of compound of formula (IVb).
In an embodiment, the palladium catalyst used can be heterogenous catalyst or homogenous catalyst.
In an embodiment, the homogenous palladium catalyst used is [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).
In an embodiment, the compound of formula (Va) wherein Q is carboxylic acid group is used.
In an embodiment, the compound of formula (Va) wherein Q is derivative of carboxylic acid group.
In an embodiment, the compound of formula (Va) is 3-Difluoromethyl-1-methylpyrazole-4-carbonyl chloride.
In an embodiment, the step i) and ii) of the process of the present invention is carried out in an alcoholic solvent.
The alcoholic solvent comprises of alcohol selected from C3 to C8 alcohols or its mixture.
In an embodiment, the alcoholic solvent is n-butanol.
In another embodiment, the alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent.
In another embodiment, the second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In an embodiment, the alcoholic solvent is mixture of first and second solvent independently selected from C3 to C8 alcohols.
In another embodiment, the alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In a preferred embodiment, the alcoholic solvent is mixture of butanol and water.
In an embodiment, the ratio of butanol to water is in range of about 1:0.1 to about 1:10, preferably the ratio of butanol to water is in range of 1:0.1 to 1:5.
According to an aspect of the present invention, there is provided a process for preparation of Boscalid of formula (Ic) or salts thereof,

comprising steps of
i) reacting a boronic acid of formula (IIc) with a compound of formula (IIIa) in presence of a palladium catalyst to obtain a compound of formula (IVc)

wherein X2 is selected from halogen; Y is hydrogen or protecting group;
ii) reacting the compound of formula (IVc) with a compound of formula (Vb) to obtain Boscalid of formula (Ic);

wherein Q is selected from carboxylic acid group or a derivative thereof;
wherein each step of the process is carried out in an alcoholic solvent.
In an embodiment, the compound of formula (IVc) is isolated.
In an embodiment, the process is carried out in situ without requiring step of isolation and purification of compound of formula (IVc).
In an embodiment, the compound of formula (IVc) is N-(4'-Chloro-1,1'-biphenyl-2-yl)acetamide.
In an embodiment, the palladium catalyst used can be heterogenous catalyst or homogenous catalyst.
In an embodiment, the homogenous palladium catalyst used is bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.
In an embodiment, the compound of formula (Vb) wherein Q is carboxylic acid group is used.
In an embodiment, the compound of formula (Vb) wherein Q is derivative of carboxylic acid group.
In an embodiment, the compound of formula (Vb) wherein Q is carbonyl halide group is used.
In an embodiment, the compound of formula (Vb) is 2-chloronicotinoyl chloride.
In an embodiment, the step i) and ii) of the process of the present invention is carried out in an alcoholic solvent.
The alcoholic solvent comprises of alcohol selected from C3 to C8 alcohols or its mixture.
In an embodiment, the alcoholic solvent is n-butanol.
In another embodiment, the alcoholic solvent is a mixture of first solvent selected from C3 to C8 alcohols and a second solvent.
In another embodiment, the second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In an embodiment, the alcoholic solvent is a mixture of first and second solvent independently selected from C3 to C8 alcohols.
In another embodiment, the alcoholic solvent is a mixture of first solvent selected from C3 to C8 alcohols and a second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane; C3 to C8 alcohols and the like.
In a preferred embodiment, the alcoholic solvent is a mixture of butanol and water.
In an embodiment, the ratio of butanol and water is in range of about 1:0.1 to about 1:10, preferably, the ratio of butanol to water is in range of 1:0.1 to 1:5.
According to an aspect of the present invention, there is provided a process for preparation of compound of formula (IVc)

comprising
reacting a boronic acid of formula (IIc) with a compound of formula (IIIa) in presence of a palladium catalyst and an alcoholic solvent to obtain compound of formula (IVc)

wherein X2 is selected from halogen; Y is hydrogen or protecting group.
In an embodiment, the palladium catalyst used can be heterogenous catalyst or homogenous catalyst.
In an embodiment, the palladium catalyst used is heterogenous palladium catalyst.
In an embodiment, the heterogenous palladium catalyst are supported catalyst such as metallic palladium, organic or inorganic palladium compounds may be used. Suitable organic or inorganic palladium compounds are preferably palladium salts such as acetate or propionate, chloride, hydroxide, bromide, iodide, nitrate, sulfate.
In an embodiment, the heterogenous palladium catalyst used is supported on inert material such as activated carbon, aluminum oxide, barium sulfate, calcium carbonate, pumice, alumina, kieselguhr or silica gel.
In an embodiment, the palladium catalyst is selected from, but not limited to palladium black or palladium on supports, such as palladium on carbon, palladium hydroxide on carbon, palladium on barium sulfate, palladium on calcium carbonate.
In an embodiment, the supported palladium catalyst is palladium on carbon.
In an embodiment, the supported palladium catalyst contains from about 1% to about 30% by weight of palladium, based on the support material.
In an embodiment, the supported palladium catalyst contains from about 2% to about 20% by weight of palladium, based on the support material.
In an embodiment, the supported palladium catalyst contains from about 2% to about 15% by weight of palladium, based on the support material.
In an embodiment, the heterogenous palladium catalyst is used in an amount ranging from about 0.01 mol% to about 10 mol%.
In an embodiment, the palladium catalyst used is homogenous palladium catalyst.
In an embodiment, the homogenous palladium catalyst used is in the form of a complex consisting of palladium in the 0 oxidation state and a phosphine ligand.
In an embodiment, the homogenous palladium catalyst used is selected from [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) or bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.
In an embodiment, the homogenous palladium catalyst used is [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).
In an embodiment, the homogenous palladium catalyst used is bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.
The homogenous palladium catalysts used are generally produced in situ from at least one palladium (II) salt or a palladium (0) compound and the corresponding phosphine ligands.
Suitable palladium sources are for example selected from the group consisting of palladium trifluoroacetate, palladium fluoroacetylacetonate, Pd(OAc)2, Pd(OCOCH2CH3)2, Pd(OH)2, PdCl2, PdBr2, Pd(acac)2 (acac=acetylacetonate), Pd(NO3)2, Pd(dba)2, Pd2 dba3 (dba=dibenzylideneacetone), Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Li[PdCl4], Pd/C or palladium nanoparticles.
In an embodiment, the alcoholic solvent may comprise water.
In an embodiment, the alcoholic solvent used is selected from C3 to C8 alcohols or its mixture.
In an embodiment, the C3 to C8 alcohols is selected from n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol and so on.
In an embodiment, the alcoholic solvent is single solvent selected from C3 to C8 alcohols.
In an embodiment, the alcoholic solvent is n-butanol.
In another embodiment, the alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent.
In another embodiment, the second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, C3 to C8 alcohols and the like.
In an embodiment, the alcoholic solvent is a mixture of first and second solvent independently selected from C3 to C8 alcohols.
In another embodiment, the alcoholic solvent is a mixture of first solvent selected from C3 to C8 alcohols and a second solvent selected from water; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, dichloroethane; C3 to C8 alcohols and the like.
In a preferred embodiment, the alcoholic solvent is mixture of butanol and water.
The ratio of butanol to water is in range of 1:0.1 to 1:5.
In an embodiment, the purity of the carboxamide compounds obtained by the process of the present invention is greater than 90%, preferably greater than 95%.
EXAMPLES
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples provided below are merely illustrative of the invention and are not intended to limit the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention.

Example 1: Process for preparation of Fluxapyroxad of formula (Ia)
To a mixture of 337 ml of n-butanol, 49.69g of 3,4,5-trifluorophenyl boronic acid and 136.7g of potassium carbonate, was added 46.16g of 2-bromo aniline. The reaction mass was heated to 108-115°C followed by addition of 0.055g of [1,1'-Bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II). The reaction mass was then stirred and maintained at 108-115°C for 2-4 hours. After completion of reaction, the reaction mixture was filtered, and filtrate was partially concentrated to 20% v/v. To the concentrated reaction mixture was added 37.47g of N,N-dimethylaniline and 57.4g of 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride at 25-30°C. The reaction mixture formed was then stirred at room temperature for 4-6 hours. After completion of reaction, 50ml of water was added to reaction mixture and mixture was stirred for 0.5 to 1 hour. The product obtained was filtered and dried to get 85g of Fluxapyroxad with purity of 98.3% (wt/wt).
Example 2: Process for preparation of Fluxapyroxad of formula (Ia)
To a mixture of 216 ml of n-butanol and 174 ml of water was added 57.15g of 3,4,5-trifluorophenyl boronic acid, 130.6g of potassium carbonate and 50g of 2-chloro acetanilide. The reaction mass was then heated slowly to 100°C followed by addition of 0.103g of bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium. The reaction mass was then stirred and maintained at 100°C for 6-7 hours. After completion of reaction, the reaction mass was cooled to 80°C and 200ml of water was added, the mixture was stirred and layers were separated. The organic layer was subjected to deprotection by treatment with 76 ml of 30% hydrochloric acid at 25-30 °C. After completion of reaction, the mixture was washed with water, and to the organic layer obtained was then treated with 190 ml of 15% potassium carbonate solution. The mixture was stirred for 0.5 hours and layers were separated. The organic layer was concentrated to 20-25% v/v followed by addition of 73.4 ml of N,N-dimethylaniline and 59.2g of 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride at 25-30°C. The reaction mixture formed was then maintained at room temperature for 3-4 hours. After completion of reaction, 200ml of water was added to reaction mixture and mixture was stirred for 0.5 to 1 hour and then cooled to 0-5°C to obtain product. The product obtained was filtered and dried to get 94.2g of Fluxapyroxad with purity of 98.74% (wt/wt).
Example 3: Process for preparation of Bixafen of formula (Ib)
To a mixture of 40ml of n-butanol and 80ml water was added 37.74g of potassium carbonate, 6.77g of tetrabutylammonium bromide, 20.08g of 3,4 – dichloro phenyl boronic acid and 20g of 2-bromo, 4-fluoro aniline. The reaction mixture thus obtained, was heated to 65-70°C under nitrogen followed by addition of 0.040g of [1,1'-Bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II). The reaction mixture was then stirred and maintained for 6-8 hours at 65-70°C. After completion of the reaction, layers were separated and the moisture in organic layer was removed azeotropically. To the organic layer was then added 14.70 ml of N,N-dimethylaniline and 21.01g of 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride at 25-30°C. The reaction mixture thus formed was then maintained at 25-30°C for 4-5 hours. After completion of reaction, the mixture was cooled to 15°C to 20°C and dilute hydrochloric acid (7.139 ml of 30% hydrochloric acid and 100ml of water) was added to the reaction mixture. The mixture was then stirred for 0.5 to 2 hours to obtain solid precipitate which was then filtered and dried to get 33.5g of Bixafen having 98.59% purity.
Example 4: Process for preparation of N-(4'-Chloro-1,1'-biphenyl-2-yl)acetamide
To a mixture of 300ml of n-butanol, 52.83g of potassium carbonate, 20.54g of tetrabutylammonium bromide was added 49.82g of 4-chlorophenyl boronic acid and 68.19g of 2-bromo acetanilide. Then the reaction mass heated to 105-110°C followed by addition of 0.34g of 10% palladium on carbon. The reaction mass was then stirred for 5-6 hours at 105-110°C. After completion of reaction, the mixture was cooled to 50 to 55°C and filtered to remove inorganic salt and catalyst. The filtrate obtained was concentrated to obtain N-(4'-Chloro-1,1'-biphenyl-2-yl)acetamide.
Example 5: Process for preparation of Boscalid of formula (Ic)
To 25g of 2-Amino-4'-chlorobiphenyl hydrochloride obtained in example 4, was added 33.47 ml of N,N-dimethylaniline and 20g of 2-chloronicotinoyl chloride at 25-30°C. The reaction mixture thus formed was then maintained at 25-30°C for 2-3 hours. After completion of reaction, dilute hydrochloric acid was added and mixture was stirred at 15°C to 20°C for 0.5 to 1 hour to obtain solid precipitate which was then filtered and dried to get 28.7g of Boscalid having 97.6% purity.
Example 6: Process for preparation of Boscalid of formula (Ic)
To 120ml of n-butanol was added 56.2g of potassium carbonate, 19.13g of 4-chlorophenyl boronic acid and 68.19g of 2-bromo aniline. Then the reaction mass heated to 60-65°C and 0.023g of [1,1'-Bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II) was added. The reaction mass was then stirred for 5-6 hours at 60-65°C. After completion of reaction, the mixture was cooled to 50 to 55°C and filtered. To the filtrate obtained was added 18.30 ml of N,N-dimethylaniline and 22g of 2-chloronicotinoyl chloride at 25-30°C. The reaction mixture thus formed was then maintained at 25-30°C for 2-3 hours. After completion of reaction, water was added and mixture was cooled to 5-10°C to obtain solid precipitate which was then filtered and dried to get 32g of Boscalid having 97.5% purity.
,CLAIMS:
1. A process for preparation of carboxamide compound of formula (I) or salts thereof,

wherein, A is a selected from the group comprising of (A1) or (A2)

X1and X2 are independently selected from hydrogen or halogen; n is 0, 1, 2 or 3; and m is 0, 1 or 2
comprising the steps of
i) reacting a boronic acid of formula (II) with a compound of formula (III) in presence of a palladium catalyst to obtain a compound of formula (IV)

wherein Y is a selected from hydrogen or a protecting group; and X1, X2, n and m are same as defined above;
ii) reacting a compound of formula (IV) with a compound of formula (Va) or (Vb) to obtain a carboxamide compound of formula (I);

wherein Q is selected from carboxylic acid group or derivatives thereof;
wherein each step of the process is carried out in an alcoholic solvent.
2. The process as claimed in claim 1, wherein the carboxamide compound of formula (I) is selected from Fluxapyroxad, Bixafen or Boscalid; the boronic acid compound of formula (II) is selected from 3,4,5-trifluorophenyl)boronic acid, 3,4-dichlorophenylboronic acid or 4-chlorophenylboronic acid; the compound of formula (III) is selected from the compound of formula (IIIa) or (IIIb);

the compound of (IV) is selected from the compound of formula (IVa), (IVb) or (IVc);

the compound of formula (Va) is selected from 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid or 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride; the compound of formula (Vb) is selected from 2-chloronicotinic acid or 2-chloronicotinoyl chloride; and wherein X2 and Y has same definition as in claim 1.

3. The process as claimed in claim 1, wherein the palladium catalyst is selected from heterogenous catalyst or homogenous catalyst.

4. The process as claimed in claim 3, wherein the heterogenous palladium catalyst is selected from palladium catalyst supported on inert material or inorganic palladium compounds.

5. The process as claimed in claim 3, wherein the homogenous palladium catalyst is in the form of a complex consisting of palladium in the zero oxidation state and a phosphine ligand.

6. The process as claimed in claim 3, wherein the homogenous palladium catalyst is selected from [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) or bis[4-[bis(1,1-dimethylethyl) phosphino-?P]-N,N-dimethylbenzenamine] dichloropalladium.

7. The process as claimed in claim 1, wherein the step i) of the process is carried out in presence of a base selected from the group comprising of alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal and alkaline earth metal acetates, alkali metal and alkaline earth metal formates, alkali metal and alkaline earth metal alcoholates, primary, secondary and tertiary amines and mixtures thereof.

8. The process as claimed in claim 1, wherein the step i) of the process is carried out in presence of a phase transfer catalyst selected from the group comprising of a quaternary ammonium salt, an amine N-oxide compound, a quaternary phosphonium salt, a crown ether compound and a polyethylene glycol compound.

9. The process as claimed in claim 1, wherein the step ii) of reaction is carried out in presence of an acid scavenger selected from the group comprising of N, N-dimethylaniline, trimethylamine, triethylamine, diisopropylethylamine, N-methylpiperidine, pyridine, collidine, lutidine and 4-dimethylaminopyridine, and bicyclic amines.

10. The process as claimed in claim 1, wherein the alcoholic solvent is selected from C3 to C8 alcohols or mixtures thereof.

11. The process as claimed in claim 1, wherein the alcoholic solvent is n-butanol.

12. The process as claimed in claim 1, wherein the alcoholic solvent is mixture of first solvent selected from C3 to C8 alcohols and a second solvent.

13. The process as claimed in claim 14, wherein the second solvent selected from water; aromatic hydrocarbons; chlorinated hydrocarbons or alcohols.

14. The process as claimed in claim 12, wherein the ratio of first solvent to second solvent is in range of 1:0.1 to 1:10.

15. The process as claimed in claim 1, wherein the alcoholic solvent is mixture of butanol and water.