Patent Description:
Conventional processes for the production of <NUM>-Bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid are subject to several industrial concerns, such as processability, environmental hazards, high cost, reagent reactivity, and necessary specialized equipment.

<CIT> provides a method for producing a hydrazine compound which is useful as an insecticidal compound, production intermediates which can be suitably used for the production method, and methods for producing the intermediates. <CIT> discloses a process for preparing N-substituted <NUM>-pyrazole-<NUM>-carboxylic acid compounds and derivatives thereof.

The present disclosure provides novel methods useful for preparing <NUM>-Bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid and derivatives thereof. The benefits of the methods of the present disclosure compared to previous methods are numerous and include improved overall yield, reduced cost, eliminated need for mixed solvent separations, reduced waste, simplified operation complexity, and reduced process hazards.

The disclosed methods provide an overall yield of about <NUM>% with commercially available and easily handled reagents.

The invention provides a method of preparing a compound of Formula VI as defined in the claims. In particular, provided herein is a method of preparing a compound of Formula VI
<CHM>.

As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains", "containing," "characterized by" or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.

The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

The transitional phrase "consisting essentially of" is used to define a composition or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of" occupies a middle ground between "comprising" and "consisting of".

Where an invention or a portion thereof is defined with an openended term such as "comprising," it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms "consisting essentially of" or "consisting of.

Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

As used herein, the term "about" means plus or minus <NUM>% of the value.

The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.

When a group contains a substituent which can be hydrogen, for example R<NUM>, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.

The term "organic base" includes, without limitation, amine compounds (e.g., primary, secondary and tertiary amines), heterocycles including nitrogen-containing heterocycles, and ammonium hydroxide.

The term "inorganic base" includes, without limitation, inorganic compounds with the ability to react with, or neutralize, acids to form salts, such as, for example, metal salts of hydroxide, carbonate, bicarbonate and phosphate.

The term "halogenation reagent" includes, without limitation, halogens and inorganic compounds, such as, for example, bromine, NBS, and <NUM>,<NUM>-dibromo-<NUM>,<NUM>-dimethylhylhydantoin.

The term "phase transfer catalyst" includes compounds that facilitate the migration of a reactant from one phase into another phase where a reaction occurs. Phase transfer catalysis refers to the acceleration of the reaction upon the addition of the phase transfer catalyst.

The term "ester" includes, without limitation, a functional group comprising an ester bond (C(=O)-O-). In some aspects, the functional group comprising an ester bond is an alkyl (or cycloalkyl) having one to eight carbon atoms, like methyl, ethyl, <NUM> -propyl, <NUM>-propyl, <NUM> - butyl, <NUM>-methylheptyl (meptyl), etc..

The term "ether" includes, without limitation, a functional group comprising an ether bond (C-O-C).

The term "nitrile" includes, without limitation, a functional group comprising a nitrile bond (-C≡N).

The term "carboxylic acid" includes, without limitation, a functional group comprising a carboxylic acid bond (C(=O)-OH).

The term "organic acid" includes, without limitation, a functional group that confers acidity and consists of atoms selected from carbon, nitrogen, oxygen, and hydrogen.

Certain compounds formed in this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.

The following embodiments <NUM>-<NUM> illustrate the invention and embodiments <NUM>-<NUM> are for reference only.

Embodiment <NUM>. A method of preparing a compound of Formula VI, wherein
<CHM>.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the compound comprising a metal is selected from a Grignard reagent and a lithium-containing compound.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr<NUM>NMgCl, iPr<NUM>NMgBr, Et<NUM>NMgCl, TMPMgCl, TMPMgCl•LiCl, iPr<NUM>NMgCl•LiCl, iPr<NUM>NMgBr•LiCl, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the Grignard reagent is iPr<NUM>NMgCl.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent is selected from THF, toluene, <NUM>,<NUM>-dioxane, Me-THF, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent is THF.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the carbonyl-containing compound is selected from dimethylcarbonate, N,N-dimethylacetamide, carbon dioxide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the carbonyl-containing compound is carbon dioxide.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about <NUM> to about <NUM>.

Embodiment <NUM>. The method of embodiment <NUM>, wherein R<NUM> and R<NUM> of Formula III are each independently hydrogen.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the compound of Formula III, is prepared according to a method comprising.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the inorganic base is selected from powder sodium hydroxide, powder potassium hydroxide, potassium carbonate, potassium phosphate, powder sodium methoxide, powder potassium t-butoxide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-<NUM>-pyrrolidone, acetonitrile, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the phase transfer catalyst is selected from butyl ammonium chloride, tetra butyl ammonium bromide, aliquat-<NUM>, <NUM>-crown-<NUM>, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the dehalogenation reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butyl ammonium iodide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the one or more compounds of Formula I are prepared according to a method comprising.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the halogenation reagent comprises.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the inorganic base is selected from powder sodium hydroxide, sodium hydroxide solution, powder sodium acetate, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the halogenation reagent is a mixture of about <NUM> part by weight hydrogen peroxide and about <NUM> parts by weight hydrogen bromide.

The compound of Formula III may be prepared by a method as defined in Embodiments <NUM>-<NUM> below.

Embodiment <NUM>. A method of preparing a compound of Formula III, wherein
<CHM>.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent C) is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-<NUM>-pyrrolidone, acetonitrile, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about <NUM> to about <NUM>.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent d) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about <NUM> to about <NUM>.

The compound of Formula II may be prepared by a method as defined in Embodiments <NUM>-<NUM> below.

Embodiment <NUM>. A method of preparing a compound of Formula II, wherein
<CHM>.

The compound of Formula I may be prepared by a method as defined in Embodiments <NUM>-<NUM> below.

Embodiment <NUM>. A method of preparing one or more compounds of Formula I, wherein
<CHM>.

Compounds of Formula II-A can be prepared by a method as defined in Embodiments <NUM>-<NUM> below.

Embodiment <NUM>. A method of preparing a compound of Formula II-A, wherein
<CHM>.

Embodiment <NUM>. The method of embodiment <NUM>, wherein M is selected from lithium, sodium, potassium, calcium, and magnesium.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the compound of Formula II-A is
<CHM>.

In one aspect, a compound of Formula VI is prepared according to a method represented by Scheme <NUM>. The R groups are as defined anywhere in this disclosure.

In one aspect, a compound of Formula VI is prepared according to a method represented by Scheme <NUM>. The R groups are as defined anywhere in this disclosure. Formula IA and Formula IB represent two distinct compounds of Formula I.

In one aspect, <NUM>-Bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid is prepared according to a method represented by Scheme <NUM>.

At least one distinct compound of Formula I may be prepared according to a method represented by Scheme <NUM>. The R groups are as defined anywhere in this disclosure.

This method includes reacting pyrazole with a halogenation reagent in water and optionally in the presence of an inorganic base. In one embodiment, the halogenation reagent is selected from hydrogen peroxide/HBr, bromine (Br<NUM>), N-bromosuccinimide (NBS), <NUM>,<NUM>-dibromo-<NUM>,<NUM>-dimethylhylhydantoin, hydrogen peroxide/NaBr, hydrogen peroxide/KBr, hydrogen peroxide/Br<NUM>, and combinations thereof. In another embodiment, the halogenation reagent is hydrogen peroxide/HBr. In one embodiment, the inorganic base is selected from powder sodium hydroxide, sodium hydroxide solution, powder sodium acetate, and combinations thereof. In another embodiment, there is no base. In one embodiment, the reaction temperature is in the range from about <NUM> to about <NUM>. In another embodiment, the reaction temperature is in the range from about <NUM> to <NUM>. The relative amounts of distinct compounds of Formula I produced by the reaction can be controlled according to the ratio of hydrogen peroxide/HBr. In one embodiment, hydrogen bromide and hydrogen peroxide and pyrazole are present in a ratio in the range from about <NUM> eq: <NUM> eq: <NUM> eq to about <NUM> eq: <NUM> eq: <NUM> eq. In another embodiment, hydrogen bromide and hydrogen peroxide and pyrazole are present in a ratio of <NUM> eq: <NUM> eq: <NUM> eq. In one embodiment, the halogenation reagent is a mixture of about <NUM> part by weight hydrogen peroxide and about <NUM> part by weight hydrogen bromide. In another embodiment, the halogenation reagent is a mixture of about <NUM> part by weight hydrogen peroxide and about <NUM> parts by weight hydrogen bromide. In another embodiment, the halogenation reagent is a mixture of about <NUM> part by weight hydrogen peroxide and about <NUM> parts by weight hydrogen bromide.

A compound of Formula II may be prepared according to a method represented by Scheme <NUM>. The R groups are as defined anywhere in this disclosure.

This method includes reacting at least one distinct compound of Formula I with a dehalogenation reagent in a solvent in the presence of a reducing agent. In one embodiment, the solvent is selected from water, acetic acid, toluene, N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide(DMAc), and combinations thereof. In a preferred embodiment, the solvent is water. In another embodiment, the dehalogenation reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butyl ammonium iodide (TBAI), and combinations thereof. In another embodiment, the dehalogenation reagent is potassium iodide. In one embodiment, the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulphate, and combinations thereof. In another embodiment, the reducing agent is sodium sulfite. In one embodiment, the reaction temperature is in the range from about <NUM> to about <NUM>. In another preferred embodiment, the reaction temperature ranges from about <NUM> to about <NUM>.

A compound of Formula II-A may be prepared according to a method represented by Scheme <NUM>. The R groups are as defined anywhere in this disclosure. <CHM>
<CHM>.

The compound of Formula II-A may be a metal salt of Formula II. The bond between M and N may be an ionic bond. M may be selected from alkali metals and alkaline metals. M may be selected from lithium, sodium, and potassium, such as sodium. Alternatively, M may be selected from calcium and magnesium.

For example, the compound of Formula II-A can be
<CHM>.

This method includes reacting at least one distinct compound of Formula I with a dehalogenation reagent in a solvent in the presence of a reducing agent. The solvent may be selected from water, acetic acid, toluene, N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide(DMAc), and combinations thereof, such as water. The dehalogenation reagent may be selected from sodium iodide, iodine, potassium iodide, tetra-n-butyl ammonium iodide (TBAI), and combinations thereof. The dehalogenation reagent may be potassium iodide. The reducing agent may be selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulphate, and combinations thereof, such as sodium sulfite. The reaction temperature may be in the range from about <NUM> to about <NUM>, such as the reaction temperature ranging from about <NUM> to about <NUM>.

According to the invention, a compound of Formula III is prepared according to a method represented by Scheme <NUM>. The R groups are as defined anywhere in this disclosure. <CHM>
<CHM>.

This method includes mixing a compound of Formula II with a compound of Formula IV in a solvent in the presence of an inorganic base and optionally an additive. In one embodiment, the inorganic base is selected from powder sodium hydroxide, powder potassium hydroxide, potassium carbonate, potassium phosphate, powder sodium methoxide, powder potassium t-butoxide, and combinations thereof. In one embodiment, the solvent is selected from toluene, N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide (DMAc) and N-methyl-<NUM>-pyrrolidone (NMP), acetonitrile, and combinations thereof. In another embodiment, the solvent is toluene. In one embodiment, the reaction temperature is in the range from about <NUM> to about <NUM>. In another embodiment, the reaction temperature is in the range from about <NUM> to about <NUM>. In another embodiment, the temperature is <NUM> to about <NUM>.

This aspect include mixing a compound of Formula III with CO<NUM> in a solvent in the presence of a base reagent and optionally an additive. In one embodiment, the base reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, LDA, nBuLi, iPr<NUM>NMgCl, iPr<NUM>NMgBr, Et<NUM>NMgCl, TMPMgCl, TMPMgCl•LiCl, iPr<NUM>NMgCl•LiCl, iPr<NUM>NMgBr•LiCl, and combinations thereof. In another embodiment, the base reagent is iPr<NUM>NMgCl. In one embodiment, the solvent is selected from THF, toluene, <NUM>,<NUM>-dioxane, Me-THF, and combinations thereof. In another embodiment, the solvent is THF. In one embodiment, the reaction temperature is in the range from about <NUM> to about <NUM>. In another embodiment, the temperature is in the range from about <NUM> to about <NUM>.

Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. The starting material for the following Examples may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples. It also is understood that any numerical range recited herein includes all values from the lower value to the upper value. For example, if a range is stated as <NUM>-<NUM>, it is intended that values such as <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM>, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.

<NUM> grams of pyrazole was dissolved in <NUM> water and charged to a reactor with <NUM> of <NUM>% hydrogen bromide solution. <NUM> of <NUM>% hydrogen peroxide was added drop-wise at <NUM> over <NUM> hours. The reaction temperature was controlled at <NUM>-<NUM>. After reaction, the product was precipitated as a solid, and then the reaction mixture was quenched with <NUM>% sodium sulfite. After filtration and drying, <NUM> of high purity (<NUM>%, LC Area) of a mixture of <NUM>,<NUM>,-dibromo-<NUM>-pyrazole and <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole is obtained (the ratio of <NUM>,<NUM>-dibromo-<NUM>-pyrazole to <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole = <NUM>:<NUM>, LC Area).

<NUM> grams of pyrazole was dissolved in water and then sodium hydroxide was added at <NUM> to obtain the corresponding pyrazole sodium salt. Next, <NUM> of bromine was added drop-wise at <NUM> over <NUM> hours. The reaction temperature was controlled at <NUM>-<NUM>. After reaction, the product was precipitated as a solid, and then the reaction mixture was quenched with <NUM>% sodium sulfite. After filtration and drying, <NUM> of high purity (<NUM>%, LC Area) of <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole was obtained.

<NUM> grams of a mixture of <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole and <NUM>,<NUM>,-dibromo-<NUM>-pyrazole (the ratio of <NUM>,<NUM>-dibromo-<NUM>-pyrazole to <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole = <NUM>:<NUM>, LC Area), <NUM> of Na<NUM>SO<NUM> in <NUM> water were reacted at <NUM>-<NUM> for <NUM> hours to complete reaction. After completion of the reaction, the reaction mixture was extracted with methyl isobutyl ketone (MIBK), and concentrated under vacuum at <NUM>-<NUM> to obtain <NUM>-bromo-<NUM>-pyrazole as a solid.

<NUM> grams of <NUM>-bromo-<NUM>-pyrazole and <NUM> of <NUM>% NaOH solution were reacted in the presence of toluene at a temperature of <NUM>-<NUM>. Water was removed by azetropic distillation under reflux temperature to yield the corresponding <NUM>-bromo-<NUM>-pyrazole sodium salt. Then, toluene and <NUM> of <NUM>,<NUM>-dichloropyridine were added and the mixture was reacted at <NUM>-<NUM>. After reaction, the reaction mixture was quenched with water and the organic layer was separated. The organic layer was then washed with water and concentrated under vacuum at <NUM>-<NUM> to obtain <NUM>-(<NUM>-bromo-<NUM>-pyrazol-<NUM>-yl)-<NUM>-chloropyridine as a solid.

<NUM> grams of <NUM>-(<NUM>-bromo-<NUM>-pyrazol-<NUM>-yl)-<NUM>-chloropyridine was dissolved in THF then iPr<NUM>NMgCl (in situ MeMgCl and iPr<NUM>NH) was added at <NUM> to yield the corresponding <NUM>-(<NUM>-bromo-<NUM>-pyrazol-<NUM>-yl)-<NUM>-chloropyridine magnesium salt. After <NUM> hours, <NUM> of DMC was added drop-wise at room temperature over <NUM> hours. The reaction temperature was controlled at <NUM>-<NUM>. After reaction, THF and DMC were distilled off under reduced pressure, and then the reaction mixture was quenched with water. Next, toluene was added. After separation and concentration, <NUM> of high purity (<NUM>%, LC Area) of methyl <NUM>-bromo-<NUM>-(<NUM>-chloropyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylate was obtained.

<NUM> grams of methyl <NUM>-bromo-<NUM>-(<NUM>-chloropyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylate and a caustic soda solution in <NUM> of toluene were charged to a flask at <NUM>. The the mixture was kept at <NUM>-<NUM> for <NUM> hours to complete reaction. The aqueous phase was washed with toluene twice. Dilute H<NUM>SO<NUM> was used to adjust pH to about <NUM>. After filtration and drying, <NUM> (<NUM>%, LC Area) of <NUM>-bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid was obtained.

<NUM> grams of <NUM>-(<NUM>-bromo-<NUM>-pyrazol-<NUM>-yl)-<NUM>-chloropyridine was dissolved in THF and then iPr<NUM>NMgCl, obtained in situ by separately adding MeMgCl and iPr<NUM>NH, was added at <NUM> to yield the corresponding <NUM>-(<NUM>-bromo-<NUM>-pyrazol-<NUM>-yl)-<NUM>-chloropyridine magnesium salt. After <NUM> hours, CO<NUM> gas was added at room temperature over <NUM> hour. The reaction temperature was controlled at <NUM>-<NUM>. After reaction, THF was distilled off under reduced pressure, and then the reaction mixture was quenched with water. Next, toluene was added. After separation and concentration, <NUM> of high purity (<NUM>%, LC Area) of <NUM>-bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid was obtained.

Claim 1:
A method of preparing a compound of Formula VI
<CHM>
wherein each of R<NUM> - R<NUM> is independently selected from hydrogen and halogen; and
R<NUM> is an organic acid, the method comprising
I) forming a mixture comprising
A) a compound of Formula III
<CHM>
wherein R<NUM> is hydrogen; and
each of R<NUM> - R<NUM> is independently selected from hydrogen and halogen;
B) a carbonyl-containing compound;
C) a solvent;
D) a compound comprising a metal; and
E) optionally an additive; and
II) reacting the mixture; and
wherein the compound of Formula III is prepared by mixing a compound of Formula II with a compound of Formula IV in a solvent in the presence of an inorganic base and optionally an additive;
wherein the compound of Formula II has the structure:
<CHM>
wherein each of R<NUM>, R<NUM>, and R<NUM> is independently selected from hydrogen and halogen; and
wherein at least one of R<NUM>, R<NUM>, and R<NUM> is hydrogen;
wherein the compound of Formula IV has the structure:
<CHM>
wherein each of R<NUM> - R<NUM> is independently selected from hydrogen and halogen; and
wherein the compound of Formula II is formed by
i) forming a mixture comprising
a) one or more compounds of Formula I
<CHM>
wherein each of R<NUM>, R<NUM>, and R<NUM> is independently selected from halogen and hydrogen; and
wherein at least two of R<NUM>, R<NUM>, and R<NUM> are halogen;
b) optionally a dehalogenation reagent;
c) a reducing agent; and
d) a solvent; and
ii) reacting the mixture.