EA046889B1 - METHODS FOR OBTAINING 5-BROMO-2-(3-CHLOROPYRIDIN-2-YL)-2H-PYRAZOLE-3-CARBOXYLIC ACID - Google Patents

Description

Cross reference to related application

This application claims the benefit of US Provisional Patent Application No. 62/916832, filed October 18, 2019, and US Provisional Patent Application No. 62/931310, filed November 6, 2019.

Field of technology to which the invention relates

The present invention is directed to new methods for the synthesis of 5-bromo-2-(3-chloropyridin-2-yl)-2Hpyrazole-3-carboxylic acid. The compounds produced by the methods disclosed herein are useful for the preparation of certain anthranilamide compounds that are of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole.

State of the art

Traditional methods for the production of 5-bromo-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid are characterized by some production problems, such as processability, harmful effects on the environment, high costs, reactivity of reagents and necessary specialized equipment.

The present invention provides new methods useful for the preparation of 5-bromo-2-(3chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid and its derivatives. The methods of the present invention have a number of advantages over previous methods and these include increased overall yield, reduced costs, elimination of the need to separate mixed solvents, reduced waste, simplified operation and reduced process risks.

The disclosed methods provide an overall yield of approximately 50% using commercially available and easy to use reagents.

Short description

In one aspect, this document provides a method for preparing a compound of formula VI

(formula VI), wherein each of R5-R10 is independently selected from hydrogen and halogen and

R ₁₃ is an organic acid, the method comprising I) forming a mixture containing A) a compound of formula V

(formula V) wherein R5-R10 are each independently selected from hydrogen and halogen; R12 is selected from ether, ester and nitrile and

- 1 046889 where the compound of formula V is prepared in accordance with a method comprising:

i) forming a mixture containing:

a) compound of formula III

(formula III) where R ₄ represents hydrogen;

R5 to R10 are each independently selected from hydrogen and halogen; and wherein the compound of formula III is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) a compound of formula II,

(formula II) wherein R ₄ , R 5 and R ₆ are each independently selected from hydrogen and halogen;

wherein at least one of R4, R5 and _R6 is hydrogen and wherein the compound of formula II is prepared in accordance with a process comprising:

ia) forming a mixture containing aa) a compound of formula VIII

(formula VIII) wherein R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen and wherein at least one of R15, R ₁₆ and R ₁₇ is halogen;

bb) solvent and cc) inorganic base; and ii) causing the mixture to react; BB) compound of formula IV

(formula IV) wherein R ₇ -R 11 are each independently selected from hydrogen and halogen; CC) solvent;

DD) inorganic base and

- 2 046889

EE) optional additive; And

IIA) providing a reaction in the mixture;

b) solvent;

c) organic compound;

d) compound containing metal; And

e) optionally an additive; and ii) causing the mixture to react; And

B) metal hydroxide; And

ii) ensuring the reaction in the mixture.

In one aspect, this document provides a method for preparing a compound of formula VI

(formula VI) wherein R5-R10 are each independently selected from hydrogen and halogen; and R13 is an organic acid, the method comprising: i) forming a mixture containing:

A) compound of formula III

(formula III) wherein R4 is hydrogen;

R5 to R10 are each independently selected from hydrogen and halogen; and wherein the compound of formula III is prepared in accordance with a method comprising:

i) forming a mixture containing:

a) a compound of formula II,

(formula II) wherein R4, R5 and R6 are each independently selected from hydrogen and halogen;

where at least one of R4, R5 and _R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) compound of formula VIII

- 3 046889

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

BB) solvent and

CC) inorganic base; And

IIa) providing a reaction in the mixture;

b) compound of formula IV

wherein each of R7-R11 is independently selected from hydrogen and halogen;

c) solvent;

d) an inorganic base and

e) optionally an additive; and ii) causing the mixture to react;

B) carbonyl-containing compound;

C) solvent;

D) a compound containing metal, and

E) optionally an additive; And

ii) ensuring the reaction in the mixture.

In one aspect, this document provides a method for preparing a compound of formula II

wherein R ₄ , R ₅ and R ₆ are each independently selected from hydrogen and halogen; and wherein at least one of _R4 , R5 and R6 is hydrogen, the method comprising:

I) forming a mixture containing A) a compound of formula VIII

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

B) solvent and

C) inorganic base; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of formula VII

- 4 046889

wherein R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle, and substituted or unsubstituted heterocycle, the method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) an organosulfur compound, C) optionally a solvent, and D) optionally a base; and ii) causing the mixture to react.

In one aspect, this document provides a method for preparing a compound of formula VIII

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and wherein at least one of R15, R ₁₆ and R ₁₇ is halogen, the method comprising

I) forming a mixture containing: A) a compound of formula VII

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of Formula V

(formula V) wherein R5-R10 are each independently selected from hydrogen and halogen; and R12 is selected from ether, ester and nitrile, the method comprising:

i) forming a mixture containing:

a) compound of formula III

- 5 046889

(formula III) where R ₄ represents hydrogen;

R5 to R10 are each independently selected from hydrogen and halogen; and wherein the compound of formula III is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) compound of formula II

(formula II) wherein R4, R5 and R6 are each independently selected from hydrogen and halogen;

where at least one of R4, R5 and _R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

ia) forming a mixture containing:

aa) compound of formula VIII

¹⁷ (formula VIII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

bb) solvent and cc) inorganic base; and ii) causing the mixture to react;

BB) compound of formula IV

(formula IV) wherein R7 to R11 are each independently selected from hydrogen and halogen; CC) solvent;

DD) inorganic base and

EE) optional additive; and IIA) causing the mixture to react;

- 6 046889

b) solvent;

c) organic compound;

d) a compound containing metal, and

e) optionally an additive; and ii) causing the mixture to react.

In one aspect, this document provides a method for preparing a compound of formula III

(formula III) where R ₄ represents hydrogen; and each of R5 to R10 is independently selected from hydrogen and halogen, the method comprising:

i) forming a mixture containing:

a) compound of formula II

(formula II) wherein R4, R5 and R6 are each independently selected from hydrogen and halogen;

where at least one of R4, R5 and _R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) compound of formula VIII

where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

BB) solvent and

CC) inorganic base; And

IIa) providing a reaction in the mixture;

b) compound of formula IV

- 7 046889 where each of R7-R11 is independently selected from hydrogen and halogen;

c) solvent;

d) an inorganic base and

e) optionally an additive; and ii) causing the mixture to react.

In one aspect, provided herein is a method for preparing a compound of formula II-A

H (formula II-A), where M is selected from alkali metals and alkaline earth metals; R4, R5 and _R6 are each independently selected from hydrogen and halogen; and wherein at least one of _R4 , R5 and _R6 is hydrogen, the method comprising:

I) forming a mixture containing:

A) compound of formula VIII

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

B) solvent and

C) inorganic base; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a compound of formula II-A

^m (formula II-A), where M is selected from alkali metals and alkaline earth metals; R4, R5 and R6 are each independently selected from hydrogen and halogen; and where at least one of R ₄ , R ₅ and R ₆ is hydrogen.

Detailed Description of the Invention

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

The transition phrase consisting of excludes any unspecified element, step or ingredient. If the said phrase is present in a claim, it will limit the inclusion in the claim of materials other than those specified, excluding impurities typically associated with them. If the phrase consisting of appears in the wording of a distinctive part of a claim rather than immediately after a restrictive part, it limits only the element set forth in that wording; other elements are not generally excluded from the claims.

The transition phrase essentially consisting of is used to define a composition or process that includes materials, steps, features, components or elements in addition

- 8 046889 tion to those literally disclosed, provided that such additional materials, steps, features, components or elements do not materially affect the main feature(s) and new feature(s) of the claimed invention. The term essentially consisting of is a compromise between containing and consisting of.

If an invention or part thereof is defined by an open term such as containing, it should be understood that (unless otherwise stated) the description is to be interpreted as describing such invention using the terms essentially consisting of or consisting of.

Also, unless explicitly stated otherwise, or refers to an inclusive or rather than an exclusive or. For example, the condition A or B is satisfied by any of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

Moreover, an element or component of the present invention in the singular form is intended to be non-limiting with respect to the number of representations (ie, repetitions) of the element or component. Therefore, the singular form should be considered to include one or at least one element or component, and the singular form of the element or component also includes the plural form if it is obvious that the number is not intended to be singular.

As used herein, the term approximately means plus or minus 10% of the stated value.

The term halogen, either alone or in compound words such as haloalkyl, includes fluorine, chlorine, bromine or iodine atoms. Additionally, when used in compounds such as haloalkyl, said alkyl may be partially or completely replaced by halogen atoms, which may be the same or different.

If the group contains a substituent which may be hydrogen, for example R ⁴ , then when the substituent is hydrogen, it is understood that it is equivalent to the specified group, which is unsubstituted.

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

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

The term halogenating agent includes, without limitation, halogens and inorganic compounds such as, for example, bromine, NBS and 1,3-dibromo-5,5-dimethylgylhydantoin.

The term phase transfer catalyst includes compounds that promote the transfer of a reactant from one phase to another phase where a reaction occurs. Phase transfer catalysis refers to the acceleration of a reaction by adding a phase transfer catalyst.

The term ester includes, without limitation, a functional group containing an ester linkage (C(=O)-O-). In some aspects, the functional group containing the ester linkage is an alkyl (or cycloalkyl) containing from one to eight carbon atoms, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-methylheptyl (meptyl) etc.

The term ether includes, without limitation, a functional group containing an ether linkage (C-O-C).

The term nitrile includes, without limitation, a functional group containing a nitrile bond (-C=N).

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

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

Some compounds of the present invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereoisomers, atropoisomers 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 separated from the other stereoisomer(s). In addition, one skilled in the art knows how to separate, enrich and/or selectively obtain said stereoisomers.

- 9 046889

Embodiments of the present invention include the following.

Embodiment 1: Method for preparing the compound of formula VI

(formula VI) wherein R5-R10 are each independently selected from hydrogen and halogen; and R13 is an organic acid, the method comprising:

I) forming a mixture containing:

A) compound of formula V

(formula V) wherein R5-R10 are each independently selected from hydrogen and halogen;

R12 is selected from ether, ester and nitrile; and wherein the compound of formula V is prepared in accordance with a method comprising:

i) forming a mixture containing:

a) a compound of formula III,

(formula III) where R ₄ represents hydrogen;

R5 to R ₁₀ are each independently selected from hydrogen and halogen; and wherein the compound of formula III is prepared in accordance with a method comprising:

IA) forming a mixture containing:

- 10 046889

AA) a compound of formula II,

(formula II) wherein R4, _R5 and R6 are each independently selected from hydrogen and halogen;

where at least one of _R4 , _R5 and R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

ia) forming a mixture containing:

aa) a compound of formula VIII,

¹⁷ (formula VIII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

R ₁₅ , R ₁₆ and R ₁₇ are each independently selected from hydrogen and halogen; and where at least one of R ₁₅ , R ₁₆ and R ₁₇ is halogen;

bb) solvent and cc) inorganic base; and ii) causing the mixture to react;

BB) compound of formula IV

(formula IV) wherein R ₇ -R 11 are each independently selected from hydrogen and halogen;

CC) solvent;

DD) inorganic base and

EE) optional additive; And

IIA) providing a reaction in the mixture;

b) solvent;

c) organic compound;

d) a compound containing metal, and

e) optionally an additive; and ii) causing the mixture to react; And

B) metal hydroxide; And

ii) ensuring the reaction in the mixture.

Embodiment 2. The method of Embodiment 1, wherein the metal hydroxide is selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, and combinations thereof.

Embodiment 3. The method of Embodiment 2, wherein the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.

Embodiment 4. The method of Embodiment 2, wherein the alkaline earth metal hydroxide is selected from calcium hydroxide and barium hydroxide.

Embodiment 5: The method of Embodiment 1, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 90°C.

Embodiment 6. The method of Embodiment 1, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 7. The method of Embodiment 6, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl,

- 11 046889 iPr2NMgCl-LiCl, iPr2NMgBr-LiCl and their combinations.

Embodiment 8. The method of Embodiment 7, wherein the Grignard reagent is iPr ₂ NMgCl.

Embodiment 9. The method of Embodiment 6, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 10. The method of Embodiment 1, wherein the solvent b) is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 11. The method of Embodiment 10, wherein solvent b) is THF.

Embodiment 12. The method of Embodiment 1, wherein the organic compound is selected from dimethyl carbonate, H^dimethylacetamide, and combinations thereof.

Embodiment 13. The method of Embodiment 12, wherein the organic compound is dimethyl carbonate.

Embodiment 14. The method of Embodiment 1, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 60°C.

Embodiment 15. The method of Embodiment 14, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 30°C.

Embodiment 16. The method of Embodiment 1, wherein _R5 and R6 of Formula III are each independently hydrogen.

Embodiment 17. The method of Embodiment 1, wherein the inorganic base DD) is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide, and combinations thereof.

Embodiment 18. The method of Embodiment 1, wherein the solvent (CC) is selected from toluene, N-dimethylformamide, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, and combinations thereof.

Embodiment 19. The method of Embodiment 1, wherein the additive EE) is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

Embodiment 20. The method of Embodiment 19, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6, and combinations thereof.

Embodiment 21: The method of Embodiment 1, wherein process step IIA) which reacts the mixture is carried out at a reaction temperature ranging from about 100°C to about 200°C.

Embodiment 22. The method of Embodiment 1, wherein the solvent bb) is selected from THF, toluene, heptanes, Me-THF, and combinations thereof.

Embodiment 23. The method of Embodiment 1, wherein the inorganic base cc) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and combinations thereof.

Embodiment 24. The method of Embodiment 1, wherein process step iia), which reacts the mixture, is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 25. The method of Embodiment 1, wherein the compound of formula VIII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) compound of formula VII

ABOUT

JL

Ii ⁰ (formula VII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

Embodiment 26. The method of Embodiment 25, wherein the halogenating reagent includes:

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5

- 12 046889 dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 27. The method of Embodiment 25, wherein the solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 28. The method of Embodiment 25, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 29. The method of Embodiment 28, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 30. The method of Embodiment 28, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 31 The method of Embodiment 30, wherein the lithium-containing compound is nBuLi.

Embodiment 32. The method of Embodiment 25, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 33. The method of Embodiment 32, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 34. The method of Embodiment 25, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing A) pyrazole or a pyrazole derivative,

B) organosulfur compound,

C) optionally a solvent and

D) optional basis; And

ii) ensuring the reaction in the mixture.

Embodiment 35. The method of Embodiment 34, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 36. The method of Embodiment 34, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 37. The method of Embodiment 34, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 38. The method of Embodiment 34, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 39. A process for preparing a compound of formula VI (formula VI), wherein each of R ₅ -R ₁₀ is independently selected from hydrogen and halogen; and R ₁₃ is an organic acid, the method comprising:

I) forming a mixture containing:

A) compound of formula III

- 13 046889

(formula III) wherein R4 is hydrogen;

R5 to R10 are each independently selected from hydrogen and halogen; and wherein the compound of formula III is prepared in accordance with a method comprising:

i) forming a mixture containing:

a) compound of formula II

(formula II) wherein R ₄ , R 5 and R 6 are each independently selected from hydrogen and halogen;

where at least one of R4, R5 and _R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) compound of formula VIII

•a (formula VIII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

BB) solvent and

CC) inorganic base; And

IIa) providing a reaction in the mixture;

b) compound of formula IV

' 1 (Formula IV), wherein R ₇ -R 11 are each independently selected from hydrogen and halogen; c) solvent;

d) an inorganic base and

e) optionally an additive; and ii) causing the mixture to react;

- 14 046889

B) carbonyl-containing compound;

C) solvent;

D) a compound containing metal, and

E) optionally an additive; And

ii) ensuring the reaction in the mixture.

Embodiment 40. The method of Embodiment 39, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 41. The method of Embodiment 40, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 42. The method of Embodiment 41, wherein the Grignard reagent is iPr ₂ NMgCl.

Embodiment 43. The method of Embodiment 40, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 44. The method of Embodiment 39, wherein solvent C) is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 45 The method of Embodiment 44, wherein solvent C) is THF.

Embodiment 46. The method of Embodiment 39, wherein the carbonyl-containing compound is selected from dimethyl carbonate, H-dimethylacetamide, carbon dioxide, and combinations thereof.

Embodiment 47. The method of Embodiment 46, wherein the carbonyl-containing compound is carbon dioxide.

Embodiment 48. The method of Embodiment 39, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 60°C.

Embodiment 49. The method of Embodiment 48, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 30°C.

Embodiment 50. The method of Embodiment 39, wherein the inorganic base d) is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide, and combinations thereof.

Embodiment 51. The method of Embodiment 39, wherein the solvent c) is selected from toluene, H-dimethylformamide, H-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, and combinations thereof.

Embodiment 52. The method of Embodiment 39, wherein additive e) is selected from potassium iodide, phase transfer catalyst, and combinations thereof.

Embodiment 53. The method of Embodiment 52, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6, and combinations thereof.

Embodiment 54. The method of Embodiment 39, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 100°C to about 200°C.

Embodiment 55. The method of Embodiment 39, wherein the solvent (BB) is selected from THF, toluene, heptanes, Me-THF, and combinations thereof.

Embodiment 56. The method of Embodiment 39, wherein the inorganic base (CC) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof.

Embodiment 57 The method of Embodiment 39, wherein the process step Pa) which reacts the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 58. The method of Embodiment 39, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) a compound of formula VII (formula VII), wherein R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted hethe

- 15 046889 roaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

Embodiment 59. The method of Embodiment 58, wherein the halogenating reagent includes

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane, and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 60. The method of Embodiment 58, wherein the solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 61. The method of Embodiment 58, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 62. The method of Embodiment 61, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 63. The method of Embodiment 61, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 64. The method of Embodiment 63, wherein the lithium-containing compound is nBuLi.

Embodiment 65. The method of Embodiment 58, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 66. The method of Embodiment 65, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 67. The method of Embodiment 58, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) an organosulfur compound, C) optionally a solvent, and D) optionally a base; and ii) causing the mixture to react.

Embodiment 68. The method of Embodiment 67, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 69. The method of Embodiment 67, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 70. The method of Embodiment 67, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 71. The method of Embodiment 67, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 72. A process for preparing a compound of formula II (formula II), wherein R ₄ , R ₅ and R 6 are each independently selected from hydrogen and halogen; and wherein at least one of R4, _R5 and R6 is hydrogen, the method comprising:

I) forming a mixture containing:

A) compound of formula VIII

- 16 046889

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

B) solvent and

C) inorganic base; And

ii) ensuring the reaction in the mixture.

Embodiment 73. The method of Embodiment 72, wherein the solvent is selected from THF, toluene, heptanes, Me-THF, and combinations thereof.

Embodiment 74. The method of Embodiment 72, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof.

Embodiment 75. The method of Embodiment 72, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 76. The method of Embodiment 72, wherein the compound of formula VH is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) compound of formula VII

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

Embodiment 77. The method of Embodiment 76, wherein the halogenating reagent includes:

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane, and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 78. The method of Embodiment 76, wherein the solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 79. The method of Embodiment 76, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 80. The method of Embodiment 79, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 81. The method of Embodiment 79, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 82. The method of Embodiment 81, wherein the lithium-containing compound is nBuLi.

Embodiment 83. The method of Embodiment 76, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 84. The method of Embodiment 83, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 85. The method of Embodiment 76, wherein the compound of formula VII is prepared in accordance with a method comprising:

- 17 046889

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) an organosulfur compound, C) optionally a solvent, and D) optionally a base; and ii) causing the mixture to react.

Embodiment 86. The method of Embodiment 85, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 87. The method of Embodiment 85, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 88. The method of Embodiment 85, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 89. The method of Embodiment 85, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 90: Method for preparing a compound of formula VII

where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle, the method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) organosulfur compound,

C) optionally a solvent and

D) optional basis; And

ii) ensuring the reaction in the mixture.

Embodiment 91. The method of Embodiment 90, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 92. The method of Embodiment 90, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 93. The method of Embodiment 90, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 94. The method of Embodiment 90, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 95: Method for preparing a compound of formula VIII

-hg (formula VIII), where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

R ₁₅ , R ₁₆ and R ₁₇ are each independently selected from hydrogen and halogen; and wherein at least one of R ₁₅ , R ₁₆ and R ₁₇ is halogen, the method comprising:

I) forming a mixture containing:

A) compound of formula VII

- 18 046889

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

Embodiment 96. The method of Embodiment 95, wherein the halogenating reagent includes

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 97. The method of Embodiment 90, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 98. The method of Embodiment 95, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 99. The method of Embodiment 98, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 100. The method of Embodiment 98, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 101 The method of Embodiment 100, wherein the lithium-containing compound is nBuLi.

Embodiment 102. The method of Embodiment 95, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 103 The method of embodiment 102, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 104. The method of Embodiment 95, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) organosulfur compound,

C) optionally a solvent and

D) optional basis; And

ii) ensuring the reaction in the mixture.

Embodiment 105. The method of Embodiment 104, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 106. The method of Embodiment 104, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 107. The method of Embodiment 104, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 108 The method of embodiment 104, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

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Embodiment 109: Method for preparing a compound of formula V

(formula V) wherein R5 to R ₁₀ are each independently selected from hydrogen and halogen; and R ₁₂ is selected from ether, ester and nitrile, the method comprising:

i) forming a mixture containing:

a) compound of formula III

(formula III) where R ₄ represents hydrogen;

R5 to R10 are each independently selected from hydrogen and halogen; and wherein the compound of formula III is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) compound of formula II

(formula II) wherein R4, R5 and _R6 are each independently selected from hydrogen and halogen;

where at least one of R4, R5 and _R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

ia) forming a mixture containing:

aa) compound of formula VIII

- 20 046889 where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen; and where at least one of R15, R ₁₆ and R ₁₇ is halogen;

bb) solvent and cc) inorganic base; and ii) causing the mixture to react;

BB) compound of formula IV

Re

wherein each of R7-R11 is independently selected from hydrogen and halogen;

CC) solvent;

DD) inorganic base and

EE) optional additive; And

IIA) providing a reaction in the mixture;

b) solvent;

c) organic compound;

d) a compound containing metal, and

e) optionally an additive; and ii) causing the mixture to react.

Embodiment 110 The method of Embodiment 109, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 111. The method of Embodiment 110, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 112. The method of Embodiment 111, wherein the Grignard reagent is iPr ₂ NMgCl.

Embodiment 113. The method of Embodiment 110, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 114. The method of Embodiment 109, wherein solvent b) is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 115 The method of embodiment 114, wherein solvent b) is THF.

Embodiment 116. The method of Embodiment 109, wherein the organic compound is selected from dimethyl carbonate, N-dimethylacetamide, and combinations thereof.

Embodiment 117 The method of Embodiment 109, wherein the organic compound is dimethyl carbonate.

Embodiment 118. The method of Embodiment 109, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 60°C.

Embodiment 119 The method of embodiment 118, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 30°C.

Embodiment 120. The method of Embodiment 109, wherein R5 and R6 of Formula III are each independently hydrogen.

Embodiment 121. The method of Embodiment 109, wherein the inorganic base DD) is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide, and combinations thereof.

Embodiment 122. The method of Embodiment 109, wherein the solvent (CC) is selected from toluene, N-dimethylformamide, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, and combinations thereof.

Embodiment 123 The method of Embodiment 109, wherein the additive EE) is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

Embodiment 124. The method of Embodiment 123, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6, and combinations thereof.

- 21 046889

Embodiment 125 The method of Embodiment 109, wherein process step IIA) which reacts the mixture is carried out at a reaction temperature ranging from about 100°C to about 200°C.

Embodiment 126. The method of Embodiment 109, wherein the solvent bb) is selected from THF, toluene, heptanes, Me-THF, and combinations thereof.

Embodiment 127. The method of Embodiment 109, wherein the inorganic base cc) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof.

Embodiment 128 The method of Embodiment 109, wherein process step iia), which reacts the mixture, is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 129. The method of Embodiment 109, wherein the compound of formula VIII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) compound of formula VII

where R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

Embodiment 130. The method of Embodiment 129, wherein the halogenating reagent includes:

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane, and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 131. The method of Embodiment 129, wherein the solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 132. The method of Embodiment 129, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 133. The method of Embodiment 132, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 134. The method of Embodiment 132, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 135 The method of Embodiment 134, wherein the lithium-containing compound is nBuLi.

Embodiment 136. The method of Embodiment 129, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 137 The method of embodiment 136, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 138. The method of Embodiment 129, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) organosulfur compound,

C) optionally a solvent and

D) optional basis; And

ii) ensuring the reaction in the mixture.

Embodiment 139. The method of Embodiment 138, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

- 22 046889

Embodiment 140. The method of Embodiment 138, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 141. The method of Embodiment 138, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 142 The method of embodiment 138, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 143: Method for preparing a compound of formula III

where R4 represents hydrogen; and each of R ₅ -R ₁₀ is independently selected from hydrogen and halogen, the method comprising:

i) forming a mixture containing: a) a compound of formula II

H (formula II), wherein R ₄ , R ₅ and R ₆ are each independently selected from hydrogen and halogen;

where at least one of R4, _R5 and R6 is hydrogen; and wherein the compound of formula II is prepared in accordance with a method comprising:

IA) forming a mixture containing:

AA) compound of formula VIII

where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

R ₁₅ , R ₁₆ and R ₁₇ are each independently selected from hydrogen and halogen; and where at least one of R ₁₅ , R ₁₆ and R ₁₇ is halogen;

BB) solvent and

CC) inorganic base; And

IIa) providing a reaction in the mixture;

b) compound of formula IV

- 23 046889

wherein each of R7-R11 is independently selected from hydrogen and halogen;

c) solvent;

d) an inorganic base and

e) optionally an additive; and ii) causing the mixture to react.

Embodiment 144. The method of Embodiment 143, wherein R5 and R6 of Formula III are each independently hydrogen.

Embodiment 145. The method of Embodiment 143, wherein the inorganic base d) is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide, and combinations thereof.

Embodiment 146. The method of Embodiment 143, wherein the solvent c) is selected from toluene, H-dimethylformamide, H-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, and combinations thereof.

Embodiment 147. The method of Embodiment 143, wherein additive e) is selected from potassium iodide, phase transfer catalyst, and combinations thereof.

Embodiment 148. The method of Embodiment 147, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6, and combinations thereof.

Embodiment 149 The method of Embodiment 143, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 100°C to about 200°C.

Embodiment 150. The method of Embodiment 143, wherein the solvent (BB) is selected from THF, toluene, heptanes, Me-THF, and combinations thereof.

Embodiment 151. The method of Embodiment 143, wherein the inorganic base (CC) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof.

Embodiment 152 The method of Embodiment 143, wherein the process step Pa) which reacts the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 153 The method of Embodiment 143, wherein the compound of formula VIII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) compound of formula VII

ABOUT

R ₁₄ ——-S---N

Ii \- ^J θ (formula VII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; And

ii) ensuring the reaction in the mixture.

Embodiment 154. The method of Embodiment 153, wherein the halogenating reagent includes:

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane, and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 155. The method of Embodiment 153, wherein the solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 156. The method of Embodiment 153, wherein the compound containing

- 24 046889 metal, selected from a Grignard reagent and a lithium-containing compound.

Embodiment 157. The method of Embodiment 156, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 158 The method of embodiment 156, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 159 The method of Embodiment 158, wherein the lithium-containing compound is nBuLi.

Embodiment 160. The method of Embodiment 153, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 161 The method of embodiment 160, wherein the process step of reacting the mixture is observed at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 162. The method of Embodiment 153, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) organosulfur compound,

C) optionally a solvent and

D) optional basis; And

ii) ensuring the reaction in the mixture.

Embodiment 163. The method of Embodiment 162, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 164. The method of Embodiment 162, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 165. The method of Embodiment 162, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

Embodiment 166 The method of embodiment 162, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 167: Method for preparing a compound of formula II-A

H (formula II-A), where M is selected from alkali metals and alkaline earth metals; _R4 , _R5 and R6 are each independently selected from hydrogen and halogen; and wherein at least one of _R4 , _R5 and R6 is hydrogen, the method comprising:

I) forming a mixture containing:

A) compound of formula VIII

¹⁷ (formula VIII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

R ₁₅ , R ₁₆ and R ₁₇ are each independently selected from hydrogen and halogen; and where at least one of R ₁₅ , R ₁₆ and R ₁₇ is halogen;

B) solvent and

C) inorganic base; And

ii) ensuring the reaction in the mixture.

Embodiment 168. The method of Embodiment 167, wherein the solvent is selected from

- 25 046889

THF, toluene, heptanes, Me-THF and combinations thereof.

Embodiment 169. The method of Embodiment 167, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof.

Embodiment 170. The method of Embodiment 167, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 171. The method of claim 167, wherein M is selected from lithium, sodium, potassium, calcium and magnesium.

Embodiment 172. The method of Embodiment 167, wherein the compound of formula VIII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) compound of formula VII

ABOUT

JL/^ι

Y ⁰ (formula VII), where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle;

B) halogenating reagent;

C) solvent and

D) a compound containing metal; and ii) causing the mixture to react.

Embodiment 173. The method of Embodiment 172, wherein the halogenating reagent includes:

A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5dimethylgilhydantoin, sodium bromide, potassium bromide, 1,2-dibromotetrachloroethane, and combinations thereof; And

B) optionally hydrogen peroxide.

Embodiment 174. The method of Embodiment 172, wherein the solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

Embodiment 175 The method of Embodiment 172, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

Embodiment 176. The method of Embodiment 172, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr -LiCl and their combinations.

Embodiment 177 The method of Embodiment 172, wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

Embodiment 178 The method of Embodiment 177, wherein the lithium-containing compound is nBuLi.

Embodiment 179 The method of embodiment 172, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -78°C to about 0°C.

Embodiment 180. The method of Embodiment 179, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about -65°C to about -50°C.

Embodiment 181. The method of Embodiment 172, wherein the compound of formula VII is prepared in accordance with a method comprising:

I) forming a mixture containing:

A) pyrazole or pyrazole derivative,

B) organosulfur compound,

C) optionally a solvent and

D) optional basis; And

ii) ensuring the reaction in the mixture.

Embodiment 182. The method of Embodiment 181, wherein the organosulfur compound is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof.

Embodiment 183. The method of Embodiment 181, wherein the solvent is selected from toluene, xylene, heptanes, and combinations thereof.

Embodiment 184. The method of Embodiment 181, wherein the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

- 26 046889

Embodiment 185 The method of Embodiment 181, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 150°C.

Embodiment 186: Compound of Formula II-A

(formula II-A), where M is selected from alkali metals and alkaline earth metals; R ₄ , R ₅ and R ₆ are each independently selected from hydrogen and halogen; and where at least one of R4, _R5 and _R6 is hydrogen.

Embodiment 187: The connection of Embodiment 186, wherein the connection is

In one aspect, a compound of formula VI is prepared in accordance with the method presented in Scheme 1. R groups are as defined elsewhere herein.

Scheme 1.

In one aspect, a compound of formula VI is prepared in accordance with the method presented in Scheme 2. R groups are as defined elsewhere herein.

Scheme 2.

In one aspect, 5-bromo-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid is prepared in accordance with the method presented in Scheme 3.

Scheme 3.

In one aspect, 5-bromo-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid is prepared in accordance with the method presented in Scheme 4.

Scheme 4.

In one aspect, a compound of Formula VII is prepared in accordance with the method presented in Scheme 9. R groups are as defined elsewhere herein.

- 27 046889

Scheme 9.

This aspect involves allowing the pyrazole to react with the protecting group reagent, optionally in the presence of a base and optionally in an organic solvent. In one embodiment, the protecting group reagent is selected from benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, and combinations thereof. In another embodiment, the protecting group reagent is benzenesulfonyl chloride. In one embodiment, the organic solvent is selected from toluene, xylene, heptanes, or combinations thereof. In another embodiment, the organic solvent is toluene. In one embodiment, the base is selected from an organic base and an inorganic base. In another embodiment, the base is selected from pyridine, triethylamine, sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof. In another embodiment, there is no base. In one embodiment, the reaction temperature is in the range from about 20°C to about 150°C. In another embodiment, the reaction temperature is in the range from about 50°C to about 90°C.

In one aspect, a compound of Formula VIII is prepared in accordance with the method presented in Scheme 10. R groups are as defined elsewhere herein.

Scheme 10.

This aspect involves allowing a compound of Formula VII to react with a halogenating reagent in an organic solvent in the presence of a basic reagent. In one embodiment, the halogenating reagent is selected from Br ₂ , N-bromosuccinimide, 1,3-dibromo-5,5-dimethylgylhydantoin, 1,2-dibromotetrachloroethane (DBTCE), and combinations thereof. In another embodiment, the halogenating reagent is Br ₂ . In one embodiment, the organic solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof. In another embodiment, the solvent is THF. In one embodiment, the base reagent is selected from LDA, nBuLi, iP^NMgCl, iP^NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr-LiCl, and combinations thereof. In another embodiment, the base is nBuLi. In one embodiment, the reaction temperature is in the range from about -78°C to about 0°C. In another embodiment, the reaction temperature is in the range from about -65°C to about -50°C.

In one aspect, a compound of Formula II is prepared in accordance with the method presented in Scheme 11. R groups are as defined elsewhere herein.

Scheme 11.

This aspect involves allowing a compound of Formula VIII to react with an organic solvent in the presence of an inorganic base. In one embodiment, the solvent is selected from THF, toluene, heptanes, Me-THF, and combinations thereof. In another embodiment, the solvent is toluene. In one embodiment, the inorganic base is selected from NaOH, KOH, Na2CO3, K2CO3, and combinations thereof. In another embodiment, the inorganic base is NaOH. In one embodiment, the reaction temperature is in the range from about 20°C to about 150°C. In another embodiment, the reaction temperature is in the range from about 50°C to about 120°C.

In one aspect, a compound of Formula II-A is prepared in accordance with the method set forth in Scheme 12. R groups are as defined elsewhere herein.

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Scheme 12.

R

ill-Ai

In one embodiment, 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. In one embodiment, M is selected from alkali metals and alkaline earth metals. In one embodiment, M is selected from lithium, sodium and potassium. In another embodiment, M is sodium. In another embodiment, M is selected from calcium and magnesium.

In one embodiment, a compound of Formula II-A is

Vg

N_

This aspect involves allowing a compound of formula VIII to react with an organic solvent in the presence of an inorganic base. In one embodiment, the solvent is selected from THF, toluene, heptanes, Me-THF, and combinations thereof. In another embodiment, the solvent is toluene. In one embodiment, the inorganic base is selected from NaOH, KOH, Na ₂ CO3, K ₂ CO3 and combinations thereof. In another embodiment, the inorganic base is NaOH. In one embodiment, the reaction temperature is in the range from about 20°C to about 150°C. In another embodiment, the reaction temperature is in the range from about 50°C to about 120°C.

In one aspect, a compound of Formula III is prepared in accordance with the method presented in Scheme 13. R groups are as defined elsewhere herein.

Scheme 13.

run

This aspect involves 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 powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide, and combinations thereof. In one embodiment, the solvent is selected from toluene, H^dimethylformamide (DMF), H^dimethylacetamide (DMAc), \-methyl-2-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 100°C to about 200°C. In another embodiment, the reaction temperature is in the range from about 130°C to about 180°C. In another embodiment, the temperature is in the range from about 145°C to about 160°C.

In one aspect, a compound of Formula VI is prepared in accordance with the method presented in Scheme 14. R groups are as defined elsewhere herein.

- 29 046889

Scheme 14.

This aspect involves mixing a compound of formula III with CO ₂ 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, iPr2NMgCl, iPr2NMgBr, Et2NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr-LiCl, and combinations thereof. In another embodiment, the main reagent is iPr ₂ NMgCl. In one embodiment, the solvent is selected from THF, toluene, 1,4-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 0°C to about 60°C. In another embodiment, the temperature is in the range from about 0°C to about 30°C.

In one aspect, a compound of Formula V is prepared in accordance with the method presented in Scheme 15. R groups are as defined elsewhere herein.

Scheme 15.

This aspect involves mixing a compound of formula III with dimethyl carbonate (DMC) in a solvent in the presence of a base reagent and optionally an additive. In one embodiment, the organic base reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, LDA, nBuLi, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr-LiCl and their combinations. In another embodiment, the organic base is iPr2NMgCl. In one embodiment, the solvent is selected from THF, toluene, 1,4-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 0°C to about 60°C. In another embodiment, the temperature is in the range from about 0°C to about 30°C.

In one aspect, a compound of Formula VI is prepared in accordance with the method presented in Scheme 16. R groups are as defined elsewhere herein.

Scheme 16.

This aspect involves allowing a compound of formula V to react with an aqueous solution of a metal hydroxide. In one embodiment, the metal hydroxide is selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, and combinations thereof. In one embodiment, the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and combinations thereof. In one embodiment, the alkaline earth metal hydroxide is selected from calcium hydroxide, barium hydroxide, and combinations thereof. In another embodiment, the metal hydroxide is sodium hydroxide or potassium hydroxide. In one embodiment, the

- 30 046889 the reaction temperature is in the range from approximately 0°C to approximately 90°C. In another embodiment, the reaction temperature is in the range from about 60°C to about 80°C. In another embodiment, the reaction temperature is in the range from about 40°C to about 70°C.

Examples

Without further qualification, it is believed that one skilled in the art, with the aid of the above description, can implement the present invention to its fullest extent. Therefore, the following examples should be considered solely as illustrative and absolutely not limiting the present invention in any way. The starting material for the following examples does not necessarily have to be prepared through a specific preparation cycle, the procedure for which is described in the other examples. It should also be understood that any numerical range given herein includes all values in the range from the lower value to the upper value. For example, if the range is specified as 10-50, then it is assumed that values such as 12-30, 20-40 or 30-50, etc., are explicitly listed in that specification. These are examples only of what is specifically stated, and all possible combinations of numerical values between and inclusive of the listed smallest value and the largest value are to be considered as expressly stated in this application.

Example 1 Reaction to add a protecting group.

50 g of pyrazole were dissolved in 150 g of toluene, and then 29.6 g of NaOH were added and 136 g of benzenesulfonyl chloride were added. The reaction mixture was refluxed for 2 hours and then cooled to 25°C. 100 g of 5% NaHCO ₃ were added and the mixture was stirred for 1 hour, and then the organic layer was separated and distilled to obtain 147 g of Bz-protected pyrazole as a product.

Example 2: Halogenation.

g Bz-protected pyrazole was dissolved in 500 g dry THF and the mixture was cooled to -50°C. After this, 132 ml BuLi (2.5 M in hexane) was added dropwise at a temperature below -50°C. After the addition, the reaction mixture was stirred at -50°C for 1 hour and then 73.6 g of anhydrous Br ₂ was added dropwise at -50°C. After addition, the reaction was quenched with 15% HOAc and the organic layer was collected and distilled to obtain 64 g of 5-bromo-1-(phenylsulfonyl)-III-pyrazole.

Example 3 Removal of the protecting group.

5-Bromo-1-(phenylsulfonyl)-III-pyrazole was dissolved in toluene and 22 g of NaOH was added. Thereafter, the reaction mixture was refluxed for 1 hour and then the water was removed by azeotropic distillation. The mixture was then cooled to 25°C and used for subsequent steps.

Example 4. Combination reaction.

The reaction was carried out with 11.5 g of 3-bromo-III-pyrazole and 14.7 g of 40% NaOH solution in the presence of toluene and at a temperature of 150 to 160°C. The water was removed by azeotropic distillation at boiling point to obtain the corresponding 3-bromo-III-pyrazole sodium salt. Toluene and 13.5 g of 2,3-dichloropyridine were then added and the mixture was allowed to react at 150-160°C. After the reaction, the reaction mixture was quenched with water and the organic layer was separated. The organic layer was then washed with water and concentrated in vacuo at 40-45° C. to obtain 2-(3-bromo-III-pyrazol-1-yl)-3chloropyridine as a solid.

Example 5 Reaction in the presence of a Grignard reagent.

g 2-(3-bromo-III-pyrazol-1-yl)-3-chloropyridine was dissolved in THF, then iPr ₂ NMgCl (in situ MeMgCl and iPr ₂ NH) was added at 0°C to obtain the corresponding magnesium salt 2-( 3-bromo-1Hpyrazol-1-yl)-3-chloropyridine. After 2.5 hours, 52.0 g of DMC was added dropwise at room temperature over 6 hours. The reaction temperature was controlled at 20-40°C. After the reaction, THF and DMC were distilled off under reduced pressure, and then the reaction mixture was quenched with water. After this, toluene was added. After separation and concentration, 36.7 g of high purity methyl 3-bromo-1-(3-chloropyridin-2-yl)-Spirazol-5-carboxylate (90%, LC Area) was obtained.

Example 6. Hydrolysis.

30 g of methyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate and a solution of caustic soda in 90 g of toluene were added to the flask at 85°C. The mixture was maintained at a temperature of 80-85°C for 2 hours until the reaction was completed. The aqueous phase was washed twice with toluene. A dilute solution of H2SO4 was used to adjust the pH to approximately 1. After filtration and drying, 26.5 g of 5-bromo-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid (97%, LC Area) was obtained.

Example 7 Carboxylation

g 2-(3-bromo-III-pyrazol-1-yl)-3-chloropyridine was dissolved in THF and then iPr ₂ NMgCl, obtained in situ by separately adding MeMgCl and iPr ₂ NH, was added at 0°C to obtain the corresponding magnesium 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine salt. After 2.5 hours, CO2 gas was added at room temperature for 1 hour. The reaction temperature was controlled at 2040°C. After the reaction, THF was distilled off under reduced pressure and then the reaction mixture was quenched with water. After this, toluene was added. After separation and concentration, 30.0 g of high purity 5-bromo-2-(3chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid (95%, LC Area) was obtained.

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In this written description, examples are used to illustrate the present invention, including the best mode, and to enable any person skilled in the art to practice the present invention, including making and using any devices or systems and performing any methods provided. The scope of patentability of the present invention is defined by the claims and may include such other examples as may be apparent to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal claims, or if they include equivalent structural elements with minor differences from the literal claims.

Claims (13)

1. Method for preparing the compound of formula VI R ₁₃ is an organic acid, and the method includes: I) forming a mixture containing: A) compound of formula V Rs Re (formula V) wherein R5-R10 are each independently selected from hydrogen and halogen; R12 is an ester and wherein the compound of formula V is prepared according to a process comprising: i) forming a mixture containing: a) compound of formula III - 32 046889 (formula III) where R ₄ represents hydrogen; each of R5-R10 is independently selected from hydrogen and halogen 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 selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide and combinations thereof; where the compound of formula II has the structure R&Re H (Formula II) wherein R4, R5 and R6 are each independently selected from hydrogen and halogen; at least one of R4, R5 and R6 is hydrogen and the compound of formula IV has the structure wherein each of R7-R11 is independently selected from hydrogen and halogen and the compound of formula II is prepared in accordance with a method comprising: ia) forming a mixture containing: aa) a compound of formula VIII, where (Formula VIII) R14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle; each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen and wherein at least one of R15, R ₁₆ and R ₁₇ is halogen; bb) solvent; and ss) inorganic base; and iia) reacting the resulting mixture; b) a solvent selected from THF, toluene, 1,4-dioxane, Me-THF and combinations thereof; - 33 046889 c) an organic compound selected from dimethyl carbonate, N,N-dimethiacetamide and combinations thereof; d) a compound comprising a metal selected from a Grignard reagent and a lithium-containing compound; and ii) reacting the mixture at a reaction temperature ranging from about 0 to about 60°C; And B) a metal hydroxide selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, and combinations thereof; And ii) reacting the mixture at a reaction temperature ranging from about 0 to about 90°C. 2. The method according to claim 1, wherein the compound of formula III is prepared in accordance with a method comprising: IA) forming a mixture containing: AA) a compound of formula II, BB) a compound of formula IV, CC) solvent; DD) inorganic base and IIA) ensuring reaction in the mixture. 3. The method according to claim 1, wherein the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide. 4. The method according to claim 1, wherein the alkaline earth metal hydroxide is selected from calcium hydroxide and barium hydroxide. 5. The method according to claim 1, where the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr ₂ NMgCl, iPr ₂ NMgBr, Et ₂ NMgCl, TMPMgCl, TMPMgCl-LiCl, iPr ₂ NMgCl-LiCl, iPr ₂ NMgBr-LiCl and their combinations. 6. The method according to claim 5, where the Grignard reagent is iPr ₂ NMgCl. 7. The method according to claim 1, where the lithium-containing compound is selected from LDA, nBuLi and combinations thereof. 8. Method according to claim 1, wherein solvent b) is THF. 9. The method according to claim 1, where the organic compound is dimethyl carbonate. 10. The method of claim 1, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 0 to about 30°C. 11. The method according to claim 1, wherein each of R ₅ and R ₆ of formula III independently represents hydrogen. 12. A process for preparing a compound of formula VI (formula VI), wherein each of R ₅ -R 1o is independently selected from hydrogen and halogen and R ₁₃ is an organic acid, and the method includes: I) forming a mixture containing: A) compound of formula III - 34 046889 where R ₄ represents hydrogen; each of R5-R10 is independently selected from hydrogen and halogen and wherein the compound of formula III is prepared in accordance with a process comprising: i) forming a mixture containing: a) compound of formula II wherein R4, R5 and R6 are each independently selected from hydrogen and halogen; at least one of R4, R5 and _R6 is hydrogen and the compound of formula II is prepared in accordance with a method comprising: IA) forming a mixture containing: AA) compound of formula VIII where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle; each of R15, R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen and wherein at least one of R15, R ₁₆ and R ₁₇ is halogen; BB) a solvent selected from THF, toluene, heptanes, Me-THF and combinations thereof; And CC) an inorganic base selected from NaOH, KOH, Na2CO3, K2CO3 and combinations thereof; And IIa) causing the mixture to react at a temperature ranging from about 20 to about 150°C; b) compound of formula IV wherein each of R7-R11 is independently selected from hydrogen and halogen; c) solvent; d) an inorganic base; and ii) causing the mixture to react; - 35 046889 B) a carbonyl-containing compound selected from dimethyl carbonate, N,N-dimethylacetamide, carbon dioxide, and combinations thereof; C) a solvent selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof; D) a metal containing compound selected from a Grignard reagent and a lithium containing compound; And ii) causing the mixture to react at a temperature ranging from about 0 to about 30°C. 13. Method for preparing the compound of formula II Re H (formula II), wherein each of _R4 , R5 and R6 is independently selected from hydrogen and halogen and at least one of R4, R5 and R6 is hydrogen, the method comprising: I) forming a mixture containing: A) compound of formula VIII where R ₁₄ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle and substituted or unsubstituted heterocycle; each of R ₁₅ , R ₁₆ and R ₁₇ is independently selected from hydrogen and halogen and wherein at least one of R ₁₅ , R ₁₆ and R ₁₇ is halogen; B) a solvent selected from THF, toluene, heptanes, Me-THF, and combinations thereof; And C) an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and combinations thereof; And ii) ensuring the reaction in the mixture.