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.

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.

In one aspect, provided herein is a method of preparing a compound of Formula II,
<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, the method comprising.

In one aspect, provided herein is a method of preparing a compound of Formula II-A,
<CHM>.

A compound of Formula II-A is prepared in a method of the invention:
<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.

Embodiments of this invention include Embodiments <NUM>-<NUM> and Embodiments <NUM>-<NUM> and the other embodiments disclosed below are for reference only.

Compounds of Formula II prepared according to the methods of the invention can be used to prepare compounds of Formula III according to a method as defined in any of Embodiments <NUM>-<NUM> below. Compounds of Formula III can be used to prepare compounds of Formula VI according to a method as defined in any of Embodiments <NUM>-<NUM> below.

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

Embodiment <NUM>. The method of embodiment <NUM>, wherein the metal hydroxide is selected from alkali hydroxide, alkaline earth metal hydroxide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the alkali hydroxide is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the alkaline earth metal hydroxide is selected from calcium hydroxide and barium hydroxide.

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 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, and combinations thereof.

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

Embodiment <NUM>. The method of embodiment <NUM>, wherein the lithium-containing compound is nBuLi.

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

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

Embodiment <NUM>. The method of embodiment <NUM>, wherein the second solvent is selected from dimethyl carbonate, N,N-dimethyacetamide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the second solvent is dimethyl carbonate.

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 R<NUM>, 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, sodium 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, NMP, sulfolane, triglyme, diglyme 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.

Compounds of Formula III as disclosed herein can be used to prepare compounds of Formula V according to a method as defined in any of Embodiments <NUM>-<NUM> below.

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

Embodiment <NUM>-<NUM>. The method of embodiment <NUM>, wherein the solvent in d) is selected from alkanes, ethers, halogenated solvents, esters, water, and combinations thereof. In some embodiments, the halogenated solvent is selected from dichloromethane, methylene chloride, trichloroethylene, and combinations thereof. In some embodiments, the ester solvent is selected from butyl acetate, sec-butyl acetate, tert-butyl acetate, and combinations thereof. In some embodiments, the solvent is an ether solvent selected from methyl tert-butyl ether (MTBE), diethyl ether (Et2O), and combinations thereof.

Embodiment <NUM>-<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 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 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 acid is selected from H<NUM>SO<NUM>, HCl, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the compound comprising a metal is a transition metal catalyst.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the transition metal catalyst is cuprous iodide.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the cyanide reagent is selected from sodium cyanide, copper(I) cyanide, zinc cyanide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the cyanide reagent is sodium cyanide.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent is selected from N-methyl-<NUM>-pyrrolidone (NMP), acetonitrile, diglyme, triglyme, ethylene glycol, propylene glycol, ethanol, isobutanol, and alcohols and sulfolane, dimethyl carbonate, N,N-dimethyacetamide, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the solvent is N,N-dimethyacetamide or diglyme.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the additive is potassium iodide.

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, and combinations thereof.

Embodiment <NUM>. The method of embodiment <NUM>, wherein the transition metal catalyst is selected from cuprous iodide, cuprous bromide, cuprous oxide, and combinations thereof.

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

Embodiment <NUM>-I. The method of embodiment <NUM>, wherein the solvent in d) is selected from alkanes, ethers, halogenated solvents, esters, water, and combinations thereof. In some embodiments, the halogenated solvent is selected from dichloromethane, methylene chloride, trichloroethylene, and combinations thereof. In some embodiments, the ester solvent is selected from butyl acetate, sec-butyl acetate, tert-butyl acetate, and combinations thereof. In some embodiments, the solvent is an ether solvent selected from methyl tert-butyl ether (MTBE), diethyl ether (Et2O), and combinations thereof.

Embodiment <NUM> -II. 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 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>.

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

<NUM>-Bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid may be prepared according to a method represented by Scheme <NUM>.

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

This aspect includes reacting pyrazole with a halogenation reagent in water, and optionally a solvent and further 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, <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, 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 about <NUM>. In yet another embodiment, the solvent is selected from alkanes, ethers, halogenated solvents, esters, water, and combinations thereof. In some embodiments, the solvent is an ether solvent selected from methyl tert-butyl ether (MTBE), diethyl ether (Et2O), and combinations thereof.

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

This aspect includes reacting a 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 form aromatic solvents, halogenated aromatic solvents, and combinations thereof. In one embodiment, the solvent is selected from acetic acid, water, toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-<NUM>-pyrrolidone (NMP), sulfolane and combinations thereof. In another embodiment, the solvent is N,N-dimethylacetamide (DMAc). In yet another embodiment, the solvent is sulfolane. In one 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 embodiment, the reaction temperature is in the range from about <NUM> to about <NUM>.

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

The compound of Formula II-A is a metal salt of Formula II. In one embodiment, the bond between M and N is an ionic bond. M is selected from alkali metals and alkaline metals. In one embodiment, M is selected from lithium, sodium, and potassium. In another embodiment, M is potassium. In another embodiment, M is selected from calcium and magnesium.

In one embodiment, the compound of Formula II-A is
<CHM>.

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

This method includes the step of 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. The inorganic base may be selected from powder sodium hydroxide, powder potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate powder sodium methoxide, powder potassium t-butoxide, and combinations thereof, such as sodium carbonate. The solvent may be selected from toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-<NUM>-pyrrolidone (NMP), sulfolane, diglyme, triglyme and combinations thereof, such as N,N-dimethyl-acetamide (DMAc) or sulfolane. The additive may be a phase catalyst selected from butyl ammonium chloride (TBAC), tetra butyl ammonium bromide (TBAB), aliquat-<NUM>, <NUM>-crown-<NUM>, and combinations thereof, such as <NUM>-crown-<NUM>. The additive may be potassium iodide. The reaction temperature may be in the range from about <NUM> to about <NUM>. The temperature may be in the range from about <NUM> to about <NUM>.

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

This method includes mixing a compound of Formula III with dimethyl carbonate (DMC) in a solvent in the presence of a base reagent and optionally an additive. The base reagent may be selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, nBuLi, and combinations thereof, such as iPrMgBr. The solvent may be selected from tetrahydrofuran (THF), toluene, <NUM>,<NUM>-dioxane, <NUM>-methyltetrahydrofuran (Me-THF), and combinations thereof, such as THF. The reaction temperature may be in the range from about <NUM> to about <NUM>. The temperature may be in the range from about <NUM> to about <NUM>.

A compound of Formula V may be 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 III with a cyanide reagent in an aprotic, polar solvent like N-methyl-<NUM>-pyrrolidone (NMP), acetonitrile, diglyme, triglyme, ethylene glycol, propylene glycol, ethanol, isobutanol, and alcohols and sulfolane, dimethyl carbonate, N,N-dimethyacetamide, and combinations thereof, such as diglyme. in the presence of copper salt and optionally an additive. The cyanide reagent may be selected from sodium cyanide, potassium cyanide, copper(I) cyanide, zinc cyanide, and combinations thereof, such as sodium cyanide. The copper salt may be selected from cuprous iodide, cuprous bromide, cuprous oxide, and combinations thereof, such as cuprous iodide. The additive may be potassium iodide. The reaction temperature may be in the range from about <NUM> to about <NUM>. The reaction temperature may be in the range from about <NUM> to about <NUM>.

This method includes reacting a compound of Formula V with an aqueous metal hydroxide solution. The metal hydroxide may be selected from alkali hydroxide, alkaline earth metal hydroxide, and combinations thereof. The alkali hydroxide may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and combinations. The alkaline earth metal hydroxide may be selected from calcium hydroxide, barium hydroxide, and combinations thereof. The metal hydroxide may be sodium hydroxide or potassium hydroxide. The reaction temperature may be in the range from about <NUM> to about <NUM>. The reaction temperature may be in the range from about <NUM> to about <NUM>.

This method includes reacting <NUM>-bromo-<NUM>-(<NUM>-chloropyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carbonitrile in the presence of an aqueous acid solution. The acid may be selected from concentrated H<NUM>SO<NUM>, HCl, and combinations thereof, such as H<NUM>SO<NUM>. The reaction temperature may be in the range from about <NUM> to about <NUM>. The reaction temperature may be 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 and <NUM> of <NUM>% hydrogen bromide solution were charged to a reactor. <NUM> grams 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 <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole was obtained.

<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 <NUM>,<NUM>,<NUM>-tribromo-<NUM>-pyrazole, <NUM> of KI, and <NUM> of Na<NUM>SO<NUM> in <NUM> DMAc were reacted at <NUM>-<NUM> for <NUM> hours to completed reaction. After completion of the reaction, the reaction mixture was filtered, and then DMAc was distilled off under vacuum. Next, water was added to the crude product. The reaction mixture was stirred for <NUM>. The product, <NUM>,<NUM>-dibromo-<NUM>-pyrazole, was precipitated as a solid. After filtration and drying, <NUM> of high purity (<NUM>%, LC Area) of <NUM>,<NUM>-dibromo-<NUM>-pyrazole was obtained.

<NUM> grams of <NUM>,<NUM>-dibromo-<NUM>-pyrazole and <NUM> of NaOH 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>,<NUM>-dibromo-<NUM>-pyrazole sodium salt. Then, DMAc and <NUM> of <NUM>,<NUM>-dichloropyridine were added and the mixture was reacted at <NUM>-<NUM> in an autoclave to produce <NUM>-chloro-<NUM>-(<NUM>,<NUM>-dibromo-<NUM>-pyrazol-<NUM>-yl)pyridine. After reaction, the reaction mixture was filtered. The DMAc solution containing <NUM>-chloro-<NUM>-(<NUM>,<NUM>-dibromo-<NUM>-pyrazol-<NUM>-yl)pyridine could be used in subsequent steps.

<NUM> grams of CuI, <NUM> KI, and <NUM> NaCN were added to a solution of <NUM> <NUM>-chloro-<NUM>-(<NUM>,<NUM>-dibromo-<NUM>-pyrazol-<NUM>-yl)pyridine in DMAc at <NUM>-<NUM>. Next, the reaction mixture was stirred at <NUM>-<NUM> for <NUM> hours to complete reaction. DMAc was distilled off under vacuum. Toluene was added and stirred for <NUM> minutes. Next, the solution was filtered and toluene was removed under vacuum. After filtration and drying, <NUM> (<NUM>%, LC Area) of <NUM>-bromo-<NUM>-(<NUM>-chloropyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carbonitrile was obtained.

<NUM> grams of high purity (<NUM>%, LC Area) <NUM>-bromo-<NUM>-(<NUM>-chloropyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carbonitrile was dissolved in <NUM>% H<NUM>SO<NUM> solution and charged to a flask. The mixture was heated to <NUM>-<NUM> and kept at this temperature for <NUM>-<NUM> hours to complete reaction. NaOH solution was used to adjust pH to a value in the range of about <NUM> to about <NUM> to precipitate the corresponding <NUM>-bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid sodium salt. H<NUM>SO<NUM> was then used to adjust pH to a value in the range of about <NUM> to about <NUM> to precipitate <NUM>-bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid. 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>-chloro-<NUM>-(<NUM>,<NUM>-dibromo-<NUM>-pyrazol-<NUM>-yl)pyridine was dissolved in THF then iPrMgCl was added at <NUM> to yield the corresponding <NUM>-chloro-<NUM>-(<NUM>,<NUM>-dibromo-<NUM>-pyrazol-<NUM>-yl)pyridine 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 high purity (<NUM>%, LC Area) of methyl <NUM>-bromo-<NUM>-(<NUM>-chloropyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylate, <NUM> of <NUM>% NaOH solution, and <NUM> of toluene were charged to a flask and the mixture was heated to <NUM>-<NUM> and kept at this temperature for <NUM>-<NUM> hours to complete reaction. H<NUM>SO<NUM> was used to adjust pH to a value in the range of about <NUM> to about <NUM> to precipitate <NUM>-bromo-<NUM>-(<NUM>-chloro-pyridin-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxylic acid.

Claim 1:
A method of preparing a compound of Formula II,
<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, the method comprising
I) forming a mixture comprising
A) a compound of Formula I,
<CHM>
wherein each of R<NUM>, R<NUM>, and R<NUM> is independently a halogen; and
wherein the compound of Formula I is prepared according to a method comprising
i) forming a mixture comprising
a) pyrazole or a pyrazole derivative;
b) a halogenation reagent;
c) water;
d) optionally a solvent; and
e) optionally an inorganic base; and
ii) reacting the mixture;
B) optionally a dehalogenation reagent;
C) a reducing agent; and
D) a solvent; and
II) reacting the mixture.