Method for the preparation of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid

Abstract

Described herein is a novel method for the synthesis of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid from pyrazole or a pyrazole derivative. Also described herein are novel reaction intermediates.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 916,840, filed October 18, 2019, and to U.S. Provisional Patent Application No. 62 / 982,248, filed February 27, 2020.

[0002] The present disclosure is directed to a novel method for the synthesis of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid. Compounds prepared by the methods disclosed herein are useful for the preparation of certain anthranilamide compounds of interest as insecticides, such as the insecticides chlorantraniliprole and cyantraniliprole. [Background technology]

[0003] Conventional manufacturing processes for 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid are subject to several industrial concerns, such as processability, environmental hazards, high cost, reagent reactivity, and specialized equipment required.

[0004] The present disclosure provides a novel method useful for preparing 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid and its derivatives. The benefits of the disclosed method compared to previous methods are numerous, including improved overall yields, reduced costs, elimination of the need for mixed solvent separation, reduced waste, simplified operational complexity, and reduced process hazards.

[0005] The disclosed method provides an overall yield of approximately 50% using commercially available and easily handled reagents. Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the compound of formula VI [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 13 is an organic acid) A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula V [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. Compound wherein the compound of formula V is i) The following a) Formula III [ka] (In the formula, R4~R 10 are independently selected from hydrogen and halogen; At least one of R4, R5, and R6 is hydrogen. Compounds of; b) a first solvent; c) a second solvent; d) compounds containing metals; and e) Optional Additives forming a mixture comprising: ii) reacting the mixture and B) Metal hydroxide forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0007] In one aspect, the compound of formula V [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula III [ka] (In the formula, R4 is a halogen; R5~R 10 each of which is independently selected from hydrogen and halogen. Compounds of; B) the first solvent; C) a second solvent; D) compounds containing metals; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0008] In one aspect, the compound of formula V [ka] (In the formula, R5 is hydrogen; R6~R 10 each is independently a halogen; Each of R7-R9 is independently selected from hydrogen and halogen; R 12 is a nitrile) The compound of formula (1) is provided.

[0009] In one aspect, the present invention relates to a compound represented by formula III [ka] (In the formula, R4~R 10 each is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula II [ka] (In the formula, Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. Compound wherein the compound of formula II is i) The following a) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compounds of; b) optionally a dehalogenating reagent; c) a reducing agent; and d) Solvent forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) Formula IV [ka] (In the formula, R7~R 11 each of which is independently selected from hydrogen and halogen. Compounds of; C) solvent; D) an inorganic base; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0010] In one aspect, the present invention relates to a compound represented by formula II [ka] (In the formula, Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compound wherein the compound of formula I is i) The following a) pyrazole or a pyrazole derivative; b) halogenating reagents; c) water; d) optionally a solvent; and e) optionally an inorganic base forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0011] In one aspect, the compound of formula VI [ka] (In the formula, R5~R 10each is independently selected from hydrogen and halogen; R 13 is an organic acid) A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula V [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. Compound wherein the compound of formula V is i) The following a) Formula III [ka] (In the formula, R4~R 10 are independently selected from hydrogen and halogen; At least one of R4, R5, and R6 is hydrogen. Compounds of; b) cyanide reagent; c) solvent; d) compounds containing metals; and e) Optional Additives forming a mixture comprising: ii) reacting the mixture and B) Acid and forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0012] In one aspect, the compound of formula V [ka] (In the formula, R5~R10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula III [ka] (In the formula, R4 is a halogen; R5~R 10 each of which is independently selected from hydrogen and halogen. Compounds of; B) cyanide reagent; C) solvent; D) compounds containing metals; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0013] In one embodiment, the compound of formula II-A [ka] (In the formula, M is selected from alkali metals and alkaline metals; Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compound wherein the compound of formula I is i) The following a) pyrazole or a pyrazole derivative; b) halogenating reagents; c) water; d) optionally a solvent; and e) optionally an inorganic base forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; A method is provided that includes:

[0014] In one embodiment, the compound of formula II-A [ka] (In the formula, M is selected from alkali metals and alkaline metals; Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. The compound of formula (1) is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variations thereof, are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0016] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. When in a claim, such would limit 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 in the body of a claim, rather than immediately following a preamble, it limits only the elements specified in that clause; other elements are not excluded from the claim as a whole.

[0017] The transitional phrase "consisting essentially of" is used to define a composition or method that includes materials, steps, features, ingredients, or elements in addition to those literally disclosed, provided that these additional materials, steps, features, ingredients, or elements do not materially affect the basic and novel characteristics of the invention being claimed. The term "consisting essentially of" occupies a middle ground between "comprising" and "consisting of."

[0018] Where an invention or part thereof is defined with open-ended terms such as "comprising," the description should readily be construed (unless otherwise expressly stated) to also describe such invention using the terms "consisting essentially of" or "consisting of."

[0019] Further, unless expressly stated to the contrary, "or" means inclusive or and exclusive or. For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and A and B are both true (or exist).

[0020] Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open-ended regarding the number of instances (i.e., occurrences) of that element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly meant to be singular.

[0021] As used herein, the term "about" means plus or minus 10% of the value.

[0022] The term "halogen", either alone or in compound terms such as "haloalkyl", includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in compound terms such as "haloalkyl", the alkyl may be partially or fully substituted with halogen atoms, which may be the same or different.

[0023] The group is a substituent that may be hydrogen, e.g., R 4 When a group contains a substituent, such as ##STR1## then when this substituent is taken as hydrogen, this is recognized as being equivalent to said group being unsubstituted.

[0024] The term "organic base" includes, without limitation, amine compounds (eg, primary, secondary and tertiary amines), heterocycles such as nitrogen-containing heterocycles, and ammonium hydroxide.

[0025] The term "inorganic base" includes, without limitation, inorganic compounds capable of reacting with or neutralizing acids to form salts, such as metal salts of hydroxides, carbonates, bicarbonates, and phosphates.

[0026] The term "halogenating reagent" includes, without limitation, halogens and inorganic compounds, such as, for example, bromine, NBS, and 1,3-dibromo-5,5-dimethylhydantoin.

[0027] The term "phase transfer catalyst" includes compounds that facilitate the transfer of reactants from one phase to another phase in which a reaction occurs. Phase transfer catalysis refers to the acceleration of a reaction upon the addition of a phase transfer catalyst.

[0028] The term "ester" includes, without limitation, functional groups that contain an ester bond (C(=O)-O-). In some embodiments, the functional group that contains an ester bond is an alkyl (or cycloalkyl) having 1 to 8 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-methylheptyl (meptyl), and the like.

[0029] The term "ether" includes, without limitation, functional groups that contain an ether linkage (COC).

[0030] The term "nitrile" includes, without limitation, functional groups that contain a nitrile bond (-C≡N).

[0031] The term "carboxylic acid" includes, without limitation, functional groups that contain a carboxylic acid bond (C(=O)-OH).

[0032] The term "organic acid" includes, without limitation, functional groups that impart acidity and consist of atoms selected from carbon, nitrogen, oxygen, and hydrogen.

[0033] Certain compounds of the present invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Those skilled in the art will appreciate that one stereoisomer may be more active and / or show beneficial effects when enriched or separated from other stereoisomers. In addition, those skilled in the art know how to separate, enrich and / or selectively prepare said stereoisomers.

[0034] Embodiments of the present disclosure include: Embodiment 1. Formula VI [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 13 is an organic acid) A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula V [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. Compound wherein the compound of formula V is i) The following a) Formula III [ka] (In the formula, R4~R 10 are independently selected from hydrogen and halogen; At least one of R4, R5, and R6 is hydrogen. Compounds of; b) a first solvent; c) a second solvent; d) compounds containing metals; and e) Optional Additives forming a mixture comprising: ii) reacting the mixture and B) Metal hydroxide forming a mixture comprising: II) reacting the mixture; The method includes:

[0035] Embodiment 2. The method of embodiment 1, wherein the metal hydroxide is selected from alkali hydroxides, alkaline earth metal hydroxides, and combinations thereof.

[0036] Embodiment 3. The method of embodiment 2, wherein the alkali hydroxide is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0037] Embodiment 4. The method of embodiment 2, wherein the alkaline earth metal hydroxide is selected from calcium hydroxide and barium hydroxide.

[0038] Embodiment 5. The method of embodiment 1, wherein the process step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 90°C.

[0039] Embodiment 6. The method of embodiment 1, wherein the metal-containing compound is selected from a Grignard reagent and a lithium-containing compound.

[0040] Embodiment 7. The method of embodiment 6, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, and combinations thereof.

[0041] Embodiment 8. The method of embodiment 7, wherein the Grignard reagent is iPrMgBr.

[0042] Embodiment 9. The method of embodiment 6, wherein the lithium-containing compound is nBuLi.

[0043] Embodiment 10. The method of embodiment 1, wherein the first solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

[0044] Embodiment 11 The method of embodiment 10, wherein the first solvent is THF.

[0045] Embodiment 12. The method of embodiment 1, wherein the second solvent is selected from dimethyl carbonate, N,N-dimethylacetamide, and combinations thereof.

[0046] Embodiment 13 The method of embodiment 12, wherein the second solvent is dimethyl carbonate.

[0047] Embodiment 14. The method of embodiment 1, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 60°C.

[0048] Embodiment 15. The method of embodiment 14, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 30°C.

[0049] Embodiment 16 The method of embodiment 1, wherein R4, R5, and R6 of formula III are each independently hydrogen.

[0050] Embodiment 17. A compound of formula III: I) Below A) Formula II [ka] (In the formula, Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. Compounds of; B) Formula IV [ka] (In the formula, R7~R 11 each of which is independently selected from hydrogen and halogen. Compounds of; C) solvent; D) an inorganic base; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; 2. The method of embodiment 1, wherein the compound is prepared according to a method comprising:

[0051] Embodiment 18. The method of embodiment 17, wherein the inorganic base is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium t-butoxide, and combinations thereof.

[0052] Embodiment 19. The method of embodiment 17, wherein the solvent is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, NMP, sulfolane, triglyme, diglyme, and combinations thereof.

[0053] Embodiment 20. The method of embodiment 17, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

[0054] Embodiment 21. The method of embodiment 17, wherein the phase transfer catalyst is selected from butylammonium chloride, odorant tetrabutylammonium, Aliquat-336, 18-crown-6, and combinations thereof.

[0055] Embodiment 22. The method of embodiment 17, wherein the process step II) of reacting the mixture occurs at a reaction temperature in the range of about 140°C to about 200°C.

[0056] Embodiment 23. A compound of formula II: I) Below A) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compounds of; B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; 18. The method of embodiment 17, wherein the compound is prepared according to a method comprising:

[0057] Embodiment 24. The method of embodiment 23, wherein the solvent is selected from acetic acid, water, toluene, p-dichlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, N-methyl-2-pyrrolidone (NMP), and combinations thereof.

[0058] Embodiment 25. The method of embodiment 23, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.

[0059] Embodiment 26 The method of embodiment 23, wherein the dehalogenating reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide, and combinations thereof.

[0060] Embodiment 27. The method of embodiment 23, wherein the process step II) of reacting the mixture occurs at a reaction temperature in the range of about 100°C to about 180°C.

[0061] Embodiment 28. A compound of formula I, I) Below A) pyrazole or a pyrazole derivative; B) halogenating reagents; C) water; and D) optionally a solvent; and E) optionally an inorganic base forming a mixture comprising: II) reacting the mixture; 24. The method of embodiment 23, wherein the compound is prepared according to a method comprising:

[0062] Embodiment 29. The halogenating reagent is A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally, hydrogen peroxide 29. The method of embodiment 28, comprising:

[0063] Embodiment 30. The method of embodiment 28, wherein the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

[0064] Embodiment 31. The method of embodiment 28, wherein the process step II) of reacting the mixture occurs at a reaction temperature ranging from about 0°C to about 70°C.

[0065] Embodiment 32. Formula V [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula III [ka] (In the formula, R4 is a halogen; R5~R 10 each of which is independently selected from hydrogen and halogen. Compounds of; B) the first solvent; C) a second solvent; D) compounds containing metals; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; The method includes:

[0066] Embodiment 33 The method of embodiment 32, wherein the compound containing a metal is selected from a Grignard reagent and a lithium-containing compound.

[0067] Embodiment 34 The method of embodiment 33, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, and combinations thereof.

[0068] Embodiment 35 The method of embodiment 34, wherein the Grignard reagent is iPrMgBr.

[0069] Embodiment 36 The method of embodiment 33, wherein the lithium-containing compound is nBuLi.

[0070] Embodiment 37 The method of embodiment 32, wherein the first solvent is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

[0071] Embodiment 38 The method of embodiment 37, wherein the first solvent is THF.

[0072] Embodiment 39 The method of embodiment 32, wherein the second solvent is selected from dimethyl carbonate, N,N-dimethylacetamide, and combinations thereof.

[0073] Embodiment 40 The method of embodiment 39, wherein the second solvent is dimethyl carbonate.

[0074] Embodiment 41. The method of embodiment 32, wherein the method step II) of reacting the mixture occurs at a reaction temperature ranging from about 0°C to about 60°C.

[0075] Embodiment 42. The method of embodiment 41, wherein the process step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 30°C.

[0076] Embodiment 43 The method of embodiment 32, wherein R4, R5, and R6 of formula III are each independently hydrogen.

[0077] Embodiment 44. Formula V [ka] (In the formula, R5 is hydrogen; R6 and R 10 each is independently a halogen; Each of R7-R9 is independently selected from hydrogen and halogen; R 12 is a nitrile) Compound.

[0078] Embodiment 45. The compound comprises: [ka] 45. The compound of embodiment 44, wherein

[0079] Embodiment 46. Formula III [ka] (In the formula, R4~R 10 each is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula II [ka] (In the formula, Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. Compound wherein the compound of formula II is i) The following a) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compounds of; b) optionally a dehalogenating reagent; c) a reducing agent; and d) Solvent forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) Formula IV [ka] (In the formula, R7~R 11 each of which is independently selected from hydrogen and halogen. Compounds of; C) solvent; D) an inorganic base; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; The method includes:

[0080] Embodiment 47. The method of embodiment 46, wherein the inorganic base is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium t-butoxide, and combinations thereof.

[0081] Embodiment 48. The method of embodiment 46, wherein the solvent C) is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, NMP, sulfolane, diglyme, triglyme, and combinations thereof.

[0082] Embodiment 49. The method of embodiment 46, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

[0083] Embodiment 50. The method of embodiment 49, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, Aliquat-336, 18-crown-6, and combinations thereof.

[0084] Embodiment 51. The method of embodiment 46, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 140°C to about 200°C.

[0085] Embodiment 52. The method of embodiment 46, wherein the solvent d) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

[0086] Embodiment 53 The method of embodiment 46, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.

[0087] Embodiment 54 The method of embodiment 46, wherein the dehalogenating reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide, and combinations thereof.

[0088] Embodiment 55. The method of embodiment 46, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 100°C to about 180°C.

[0089] Embodiment 56. A compound of formula I, I) Below A) pyrazole or a pyrazole derivative; B) halogenating reagents; C) water; and D) optionally a solvent; and E) optionally an inorganic base forming a mixture comprising: II) reacting the mixture; 47. The method of embodiment 46, wherein the compound is prepared according to a method comprising:

[0090] Embodiment 57. The halogenating reagent is A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally, hydrogen peroxide 57. The method of embodiment 56, comprising:

[0091] Embodiment 58. The method of embodiment 56, wherein the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

[0092] Embodiment 59. The method of embodiment 56, wherein the method step II) of reacting the mixture occurs at a reaction temperature ranging from about 0°C to about 70°C.

[0093] Embodiment 60. Formula II [ka] (In the formula, Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compound wherein the compound of formula I is i) The following a) pyrazole or a pyrazole derivative; b) halogenating reagents; c) water; and d) optionally a solvent; and e) optionally an inorganic base forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; The method includes:

[0094] The method of embodiment 60, wherein the solvent in embodiment 61-Id) is selected from an alkane, an ether, a halogenated solvent, an ester, 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 (EtO), and combinations thereof.

[0095] Embodiment 61-II. The method of embodiment 60, wherein the solvent D) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

[0096] Embodiment 62. The method of embodiment 60, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.

[0097] Embodiment 63 The method of embodiment 60, wherein the dehalogenating reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide, and combinations thereof.

[0098] Embodiment 64. The method of embodiment 60, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 100°C to about 180°C.

[0099] Embodiment 65. The halogenating reagent is A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally, hydrogen peroxide The method of embodiment 60, comprising:

[0100] Embodiment 66 The method of embodiment 60, wherein the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

[0101] Embodiment 67. The method of embodiment 60, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 70°C.

[0102] Embodiment 68. Formula VI [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 13 is an organic acid) A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula V [ka] (In the formula, R5~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. Compound wherein the compound of formula V is i) The following a) Formula III [ka] (In the formula, R4~R 10 are independently selected from hydrogen and halogen; At least one of R4, R5, and R6 is hydrogen. Compounds of; b) cyanide reagent; c) solvent; d) compounds containing metals; and e) Optional Additives forming a mixture comprising: ii) reacting the mixture and B) Acid and forming a mixture comprising: II) reacting the mixture; The method includes:

[0103] Embodiment 69. The method of embodiment 68, wherein the acid is selected from H2SO4, HCl, and combinations thereof.

[0104] Embodiment 70. The method of embodiment 68, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 100°C.

[0105] Embodiment 71 The method of embodiment 68, wherein the compound containing a metal is a transition metal catalyst.

[0106] Embodiment 72 The method of embodiment 71, wherein the transition metal catalyst is cuprous iodide.

[0107] Embodiment 73 The method of embodiment 68, wherein the cyanide reagent is selected from sodium cyanide, copper(I) cyanide, zinc cyanide, and combinations thereof.

[0108] Embodiment 74 The method of embodiment 73, wherein the cyanide reagent is sodium cyanide.

[0109] Embodiment 75. The method of embodiment 68, wherein the solvent is selected from N-methyl-2-pyrrolidone (NMP), acetonitrile, diglyme, triglyme, ethylene glycol, propylene glycol, ethanol, isobutanol, and alcohols, as well as sulfolane, dimethyl carbonate, N,N-dimethylacetamide, and combinations thereof.

[0110] Embodiment 76 The method of embodiment 75, wherein the solvent is N,N-dimethylacetamide or diglyme.

[0111] Embodiment 77. The method of embodiment 68, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 120°C to about 150°C.

[0112] Embodiment 78. The method of embodiment 77, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 130°C to about 140°C.

[0113] Embodiment 79. The method of embodiment 68, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

[0114] Embodiment 80. The method of embodiment 79, wherein the additive is potassium iodide.

[0115] Embodiment 81. The method of embodiment 68, wherein R4, R5, and R6 of formula III are each independently hydrogen.

[0116] Embodiment 82. A compound of formula III: I) Below A) Formula II [ka] (In the formula, Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. Compounds of; B) Formula IV [ka] (In the formula, R7~R 11 each of which is independently selected from hydrogen and halogen. Compounds of; C) solvent; D) an inorganic base; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; 69. The method of embodiment 68, wherein the compound is prepared according to a method comprising:

[0117] Embodiment 83. The method of embodiment 82, wherein the inorganic base is selected from powdered sodium hydroxide, powdered potassium hydroxide, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium t-butoxide, and combinations thereof.

[0118] Embodiment 84. The method of embodiment 82, wherein the solvent is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and combinations thereof.

[0119] Embodiment 85. The method of embodiment 82, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

[0120] Embodiment 86 The method of embodiment 85, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, Aliquat-336, 18-crown-6, and combinations thereof.

[0121] Embodiment 87. The method of embodiment 82, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 140°C to about 200°C.

[0122] Embodiment 88. A compound of formula II: I) Below A) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compound B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; 83. The method of embodiment 82, wherein the compound is prepared according to a method comprising:

[0123] Embodiment 89. The method of embodiment 88, wherein the solvent is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

[0124] Embodiment 90. The method of embodiment 88, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.

[0125] Embodiment 91. The method of embodiment 88, wherein the dehalogenating reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide, and combinations thereof.

[0126] Embodiment 92. The method of embodiment 88, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 100°C to about 180°C.

[0127] Embodiment 93. A compound of formula I, I) Below A) pyrazole or a pyrazole derivative; B) halogenating reagents; C) water; and D) optionally a solvent; and E) optionally an inorganic base forming a mixture comprising: II) reacting the mixture; 89. The method of embodiment 88, wherein the compound is prepared according to a method comprising:

[0128] Embodiment 94. The halogenating reagent is A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally, hydrogen peroxide 94. The method of embodiment 93, comprising:

[0129] Embodiment 95. The method of embodiment 93, wherein the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

[0130] Embodiment 95-I. The method of embodiment 93, wherein the solvent is selected from an alkane, an ether, a halogenated solvent, an ester, 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.

[0131] Embodiment 96. The method of embodiment 93, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 70°C.

[0132] Embodiment 97. Formula V [ka] (In the formula, R5~R 10each is independently selected from hydrogen and halogen; R 12 is selected from ethers, esters, and nitriles. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula III [ka] (In the formula, R4 is a halogen; R5~R 10 each of which is independently selected from hydrogen and halogen. Compounds of; B) cyanide reagent; C) solvent; D) compounds containing metals; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; The method includes:

[0133] Embodiment 98 The method of embodiment 97, wherein the compound containing a metal is a transition metal catalyst.

[0134] Embodiment 99. The method of embodiment 98, wherein the transition metal catalyst is selected from cuprous iodide, cuprous bromide, cuprous oxide, and combinations thereof.

[0135] Embodiment 100. The method of embodiment 99, wherein the transition metal catalyst is cuprous iodide.

[0136] Embodiment 101 The method of embodiment 97, wherein the cyanide reagent is selected from sodium cyanide, copper(I) cyanide, zinc cyanide, and combinations thereof.

[0137] Embodiment 102 The method of embodiment 101, wherein the cyanide reagent is sodium cyanide.

[0138] Embodiment 103. The method of embodiment 97, wherein the solvent is selected from N-methyl-2-pyrrolidone (NMP), acetonitrile, diglyme, triglyme, ethylene glycol, propylene glycol, ethanol, isobutanol, and alcohols, as well as sulfolane, dimethyl carbonate, N,N-dimethylacetamide, and combinations thereof.

[0139] Embodiment 104 The method of embodiment 103, wherein the solvent is N,N-dimethylacetamide or diglyme.

[0140] Embodiment 105. The method of embodiment 97, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 120°C to about 150°C.

[0141] Embodiment 106. The method of embodiment 105, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 130°C to about 140°C.

[0142] Embodiment 107. The method of embodiment 97, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

[0143] Embodiment 108. The method of embodiment 107, wherein the additive is potassium iodide.

[0144] Embodiment 109. The method of embodiment 97, wherein R4, R5, and R6 of formula III are each independently hydrogen.

[0145] Embodiment 110. Formula II-A [ka] (In the formula, M is selected from alkali metals and alkaline metals; Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. A process for preparing a compound of formula (I), comprising the steps of: I) Below A) Formula I [ka] (In the formula, Each of R1, R2, and R3 is independently a halogen. Compound wherein the compound of formula I is i) The following a) pyrazole or a pyrazole derivative; b) halogenating reagents; c) water; and d) optionally a solvent forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; The method includes:

[0146] The method of embodiment 60, wherein the solvent in embodiment 111-Id) is selected from an alkane, an ether, a halogenated solvent, an ester, 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 (EtO), and combinations thereof.

[0147] Embodiment 111-II. The method of embodiment 110, wherein the solvent D) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

[0148] Embodiment 112. The method of embodiment 110, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.

[0149] Embodiment 113 The method of embodiment 110, wherein the dehalogenating reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide, and combinations thereof.

[0150] Embodiment 114. The method of embodiment 110, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 100°C to about 180°C.

[0151] Embodiment 115. The halogenating reagent is A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally, hydrogen peroxide The method of embodiment 110, comprising:

[0152] Embodiment 116. The method of embodiment 110, wherein the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof.

[0153] Embodiment 117. The method of embodiment 110, wherein the process step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 70°C.

[0154] Embodiment 118. The method of embodiment 110, wherein M is selected from lithium, sodium, potassium, calcium, and magnesium.

[0155] Embodiment 119. A compound of formula II-A is [ka] The method of embodiment 110,

[0156] Embodiment 120. Formula II-A [ka] (In the formula, M is selected from alkali metals and alkaline metals; Each of R4, R5, and R6 is independently selected from hydrogen and halogen; wherein at least one of R4, R5, and R6 is hydrogen. Compound.

[0157] Embodiment 121. The compound [ka] The compound of embodiment 120, wherein

[0158] In one embodiment, compounds of formula VI are prepared according to the method depicted in Scheme 1. The R groups are as defined anywhere in this disclosure. [ka]

[0159] In one embodiment, 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid is prepared according to the method depicted in Scheme 2. [ka]

[0160] In one embodiment, 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid is prepared according to the method depicted in Scheme 3. [ka]

[0161] In one embodiment, compounds of formula I are prepared according to the method depicted in Scheme 4. The R groups are as defined anywhere in this disclosure. [ka]

[0162] This aspect includes reacting the pyrazole with a halogenating reagent in the presence of water and, optionally, a solvent and further, optionally, an inorganic base. In one embodiment, the halogenating reagent is selected from hydrogen peroxide / HBr, bromine (Br2), N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, hydrogen peroxide / NaBr, hydrogen peroxide / KBr, hydrogen peroxide / Br2, and combinations thereof. In another embodiment, the halogenating reagent is hydrogen peroxide / HBr. In one embodiment, the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate, and combinations thereof. In another embodiment, no base is present. In one embodiment, the reaction temperature is in the range of about 0° C. to about 70° C. In another embodiment, the reaction temperature is in the range of about 0° C. to about 30° C. 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.

[0163] In one embodiment, compounds of formula II are prepared according to the method depicted in Scheme 5. The R groups are as defined anywhere in this disclosure. [ka]

[0164] 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 from 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-2-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-butylammonium 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 sulfate, and combinations thereof. In another embodiment, the reducing agent is sodium sulfite. In one embodiment, the reaction temperature is in the range of about 100° C. to about 180° C. In another embodiment, the reaction temperature is in the range of about 160° C. to about 180° C.

[0165] In one embodiment, compounds of formula II-A are prepared according to the method depicted in Scheme 6. The R groups are as defined anywhere in this disclosure. [ka]

[0166] 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 metals. In one embodiment, M is selected from lithium, sodium, and potassium, and in another embodiment, M is potassium. In another embodiment, M is selected from calcium and magnesium.

[0167] In one embodiment, the compound of formula II-A is [ka] It is.

[0168] 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 from 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-2-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-butylammonium 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 sulfate, and combinations thereof. In another embodiment, the reducing agent is sodium sulfite. In one embodiment, the reaction temperature is in the range of about 100° C. to about 180° C. In another embodiment, the reaction temperature is in the range of about 160° C. to about 180° C.

[0169] In one embodiment, compounds of formula III are prepared according to the method depicted in Scheme 7. The R groups are as defined anywhere in this disclosure. [ka]

[0170] This aspect includes mixing a compound of formula II with a compound of formula IV in a solvent in the presence of an inorganic base and, optionally, an additive. In one embodiment, the inorganic base is selected from powdered sodium hydroxide, powdered potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium t-butoxide, and combinations thereof. In one embodiment, the inorganic base is sodium carbonate. In one embodiment, the solvent is selected from toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), sulfolane, diglyme, triglyme, and combinations thereof. In another embodiment, the solvent is N,N-dimethyl-acetamide (DMAc). In yet another embodiment, the solvent is sulfolane. In one embodiment, the additive is a phase transfer catalyst selected from butylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), Aliquat-336, 18-crown-6, and combinations thereof. In another embodiment, the phase transfer catalyst is 18-crown-6. In another embodiment, the additive is potassium iodide. In one embodiment, the reaction temperature ranges from about 140° C. to about 200° C. In another embodiment, the temperature ranges from about 155° C. to about 175° C.

[0171] In one embodiment, compounds of formula V are prepared according to the method depicted in Scheme 8. The R groups are as defined anywhere in this disclosure. [ka]

[0172] This aspect includes the step of combining 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 base reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, nBuLi, and combinations thereof. In another embodiment, the base reagent is iPrMgBr. In one embodiment, the solvent is selected from tetrahydrofuran (THF), toluene, 1,4-dioxane, 2-methyltetrahydrofuran (Me-THF), and combinations thereof. In another embodiment, the solvent is THF. In one embodiment, the reaction temperature is in the range of about 0° C. to about 60° C. In another embodiment, the temperature is in the range of about 0° C. to about 30° C.

[0173] In one embodiment, compounds of formula V are prepared according to the method depicted in Scheme 9. The R groups are as defined anywhere in this disclosure. [ka]

[0174] This aspect includes mixing the compound of formula III with a cyanide reagent in an aprotic polar solvent such as N-methyl-2-pyrrolidone (NMP), acetonitrile, diglyme, triglyme, ethylene glycol, propylene glycol, ethanol, isobutanol, and alcohols, as well as sulfolane, dimethyl carbonate, N,N-dimethylacetamide, and combinations thereof. In one aspect, the solvent is diglyme in the presence of a copper salt and, optionally, an additive. In one embodiment, the cyanide reagent is selected from sodium cyanide, potassium cyanide, copper(I) cyanide, zinc cyanide, and combinations thereof. In another embodiment, the cyanide reagent is sodium cyanide. In one embodiment, the copper salt is selected from cuprous iodide, cuprous bromide, cuprous oxide, and combinations thereof. In another embodiment, the copper salt is cuprous iodide. In one embodiment, the additive is potassium iodide. In one embodiment, the reaction temperature is in the range of about 120° C. to about 150° C. In another embodiment, the reaction temperature is in the range of about 130°C to about 140°C.

[0175] In one embodiment, compounds of formula VI are prepared according to the method depicted in Scheme 10. The R groups are as defined anywhere in this disclosure. [ka]

[0176] This aspect includes reacting a compound of formula V with an aqueous metal hydroxide solution. In one embodiment, the metal hydroxide is selected from an alkali hydroxide, an alkaline earth metal hydroxide, and combinations thereof. In one embodiment, the alkali 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 reaction temperature is in the range of about 0° C. to about 90° C. In another embodiment, the reaction temperature is in the range of about 60° C. to about 80° C.

[0177] In one embodiment, compounds of formula VI are prepared according to the method depicted in Scheme 11. The R groups are as defined anywhere in this disclosure. [ka]

[0178] This aspect includes reacting 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonitrile in the presence of an aqueous acid solution. In one embodiment, the acid is selected from concentrated H2SO4, HCl, and combinations thereof. In another embodiment, the acid is H2SO4. In one embodiment, the reaction temperature is in the range of about 50°C to about 100°C. In another embodiment, the reaction temperature is in the range of about 75°C to about 85°C. EXAMPLES

[0179] 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 should therefore be construed as merely illustrative and not limiting the present disclosure in any way. The starting materials for the following examples may not necessarily be prepared by the specific preparative experiments whose procedures are described in other examples. Any numerical range recited herein is also understood to include all values ​​from the lower value to the higher value. For example, if a range is stated as 10-50, it is intended that values ​​such as 12-30, 20-40, or 30-50, etc. are expressly recited in this specification. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​between and including the lowest and highest values ​​recited should be considered to be expressly recited in this specification.

[0180] Example 1. Hydrogen peroxide / HBr as the halogenating agent 34 grams of pyrazole and 505.8 grams of 48% hydrogen bromide solution were charged into a reactor. 170 grams of 30% hydrogen peroxide was added dropwise at 0°C over 2 hours. The reaction temperature was controlled at 0-30°C. After the reaction, the product precipitated as a solid, and then the reaction mixture was quenched with 10% sodium sulfite. After filtration and drying, 142 grams of high purity (95%, LC area) 3,4,5-tribromo-1H-pyrazole was obtained.

[0181] Example 2. Bromine / sodium hydroxide as halogenating agent 34 grams of pyrazole was dissolved in water, then sodium hydroxide was added at 0°C to obtain the corresponding pyrazole sodium salt. Then 239.7g of bromine was added dropwise at 0°C over 2 hours. The reaction temperature was controlled at 20-40°C. After the reaction, the product precipitated as a solid, and then the reaction mixture was quenched with 10% sodium sulfite. After filtration and drying, 147g of high purity (98%, LC area) 3,4,5-tribromo-1H-pyrazole was obtained.

[0182] Example 3. Potassium iodide / sodium sulfite as dehalogenating reagent 100 grams of 3,4,5-tribromo-1H-pyrazole, 1.1 g of KI, and 62 g of Na2SO3 in 300 mL of DMAc were reacted at 160-180°C for 5 hours until completion of the reaction. After completion of the reaction, the reaction mixture was filtered and then DMAc was distilled off under vacuum. Water was then added to the crude product. The reaction mixture was stirred for 10 minutes. The product, 3,5-dibromo-1H-pyrazole, precipitated as a solid. After filtration and drying, 68 g of highly pure (98%, LC area) 3,5-dibromo-1H-pyrazole was obtained.

[0183] Example 4. Coupling reaction 22.6 grams of 3,5-dibromo-1H-pyrazole and 4.2 grams of NaOH were reacted in the presence of toluene at a temperature of 150-160°C. Water was removed by azeotropic distillation at reflux temperature to yield the corresponding 3,5-dibromo-1H-pyrazole sodium salt. Then, DMAc and 15.5 grams of 2,3-dichloropyridine were added, and the mixture was reacted in an autoclave at 150-170°C to produce 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine. After the reaction, the reaction mixture was filtered. The DMAc solution containing 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine could be used in the subsequent steps.

[0184] Example 5. Reaction in the presence of a transition metal catalyst 0.95 grams of CuI, 3.32 grams of KI, and 5.4 grams of NaCN were added to a solution of 33.8 grams of 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine in DMAc at 10-25°C. The reaction mixture was then stirred at 130-140°C for 6 hours to complete the reaction. The DMAc was distilled off under vacuum. Toluene was added and stirred for 30 minutes. The solution was then filtered and the toluene was removed under vacuum. After filtration and drying, 23.2 grams (94%, LC area) of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonitrile was obtained.

[0185] Example 6. Acidification 28.4 grams of high purity (94%, LC area) 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonitrile was dissolved in 50% H2SO4 solution and charged into a flask. The mixture was heated to 80-85°C and kept at this temperature for 3-4 hours to complete the reaction. The pH was adjusted to a value in the range of about 9 to about 10 using NaOH solution to precipitate the corresponding 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid sodium salt. H2SO4 was then used to adjust the pH to a value in the range of about 1 to about 2 to precipitate the 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid. After filtration and drying, 28.6 g (98%, LC area) of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid was obtained.

[0186] Example 7. Reaction in the presence of Grignard reagents 33.7 grams of 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine was dissolved in THF, and then iPrMgCl was added at 0°C to give the corresponding 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine magnesium salt. 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. Then, toluene was added. After separation and concentration, 33 g of high purity (90%, LC area) methyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate was obtained.

[0187] Example 8. Hydrolysis 33 grams of highly pure (90%, LC area) methyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate, 12 g of 33% NaOH solution, and 90 g of toluene were charged to a flask, and the mixture was heated to 80-85° C. and maintained at this temperature for 1-2 hours to complete the reaction. The pH was adjusted to a value in the range of about 1 to about 2 using H2SO4 to precipitate 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid.

[0188] This specification uses examples to illustrate the disclosure, including the best mode, and also to enable any person skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur 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 language of the claims, or if they include equivalent structural elements whose differences from the literal language of the claims are insubstantial.

Claims

1. Formula VI 【Chemistry 1】 (In the formula, R 5 ~R 10 each is independently selected from hydrogen and halogen; R 13 is a carboxylic acid) A process for preparing a compound of the formula (I), said process comprising the steps of: I) The following A) Formula V 【Chemistry 2】 (In the formula, R 5 ~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from esters Compound wherein said compound of formula V is i) The following a) Formula III 【Chemistry 3】 (In the formula, R 4 is a halogen, and R 10 is independently selected from hydrogen and halogen, where R 5 , and R 6 At least one of is hydrogen. Compound of b) a first solvent; c) a second solvent; d) a compound containing a metal; and e) Optional Additives forming a mixture comprising: and ii) reacting the mixture and B) metal hydroxide; forming a mixture comprising: II) reacting the mixture; and The method includes:

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

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

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

5. The method of claim 1, wherein the second solvent is selected from dimethyl carbonate, N,N-dimethylacetamide, and combinations thereof.

6. 10. The method of claim 1, wherein process step ii) of reacting the mixture occurs at a reaction temperature ranging from about 0° C. to about 60° C.

7. R of Formula III 4 , R 5 , and R 6 The method of claim 1 , wherein each is independently hydrogen.

8. The compound of formula III is I) The following A) Formula II 【Chemistry 4】 (In the formula, R 4 , R 5 , and R 6 are independently selected from hydrogen and halogen; Here, R 4 , R 5 , and R 6 At least one of is hydrogen. Compound of B) Formula IV 【Chemistry 5】 (In the formula, R 7 ~R 11 each of which is independently selected from hydrogen and halogen. Compound of C) solvent; D) an inorganic base; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; 2. The method of claim 1, prepared according to a method comprising:

9. 9. The method of claim 8, wherein the inorganic base is selected from powdered sodium hydroxide, powdered potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium t-butoxide, and combinations thereof.

10. 9. The method of claim 8, wherein the solvent is selected from toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), sulfolane, diglyme, triglyme, and combinations thereof.

11. 9. The method of claim 8, wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

12. The method of claim 11, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium chloride, Aliquat-336, 18-crown-6, and combinations thereof.

13. 9. The process of claim 8, wherein process step II) of reacting the mixture occurs at a reaction temperature in the range of about 140° C. to about 200° C.

14. The compound of formula II is I) The following A) Formula I 【Chemistry 6】 (In the formula, R 1 , R 2 , and R 3 each of which is independently a halogen. Compound of B) optionally a dehalogenating reagent; C) a reducing agent; and D) Solvent forming a mixture comprising: II) reacting the mixture; 9. The method of claim 8, wherein the composition is prepared according to a method comprising:

15. 15. The method of claim 14, wherein the solvent is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

16. The compound of formula I is I) The following A) pyrazole or a pyrazole derivative; B) a halogenating agent; C) water; D) optionally a solvent; and E) Optionally, an inorganic base forming a mixture comprising: II) reacting the mixture; 15. The method of claim 14, wherein the composition is prepared according to a method comprising:

17. The halogenating reagent is A) a reagent selected from hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally, hydrogen peroxide 17. The method of claim 16, comprising:

18. Formula V 【Chemistry 7】 (In the formula, R 5 ~R 10 each is independently selected from hydrogen and halogen; R 12 is selected from esters A process for preparing a compound of the formula (I), said process comprising the steps of: I) The following A) Formula III 【Chemistry 8】 (In the formula, R 4 is a halogen; R 5 ~R 10 each of which is independently selected from hydrogen and halogen. Compound of B) a first solvent; C) a second solvent; D) a compound containing a metal; and E) Optional Additives forming a mixture comprising: II) reacting the mixture; The method includes:

19. 20. The method of claim 18, wherein the compound containing a metal is selected from a Grignard reagent and a lithium-containing compound.

20. 20. The method of claim 19, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, and combinations thereof.

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