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

Abstract

A novel method for synthesizing 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid from pyrazole or pyrazole derivatives is described herein. Also described herein are novel reaction intermediates.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 916,840, filed on October 18, 2019, and U.S. Provisional Application No. 62 / 982,248, filed on February 27, 2020. Technical Field

[0003] The present disclosure relates to a novel method for synthesizing 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid. The compounds prepared by the methods disclosed herein can be used to prepare certain anthranilamide compounds of interest as insecticides, such as the insecticides chlorantraniliprole and cyantraniliprole. Background Art

[0004] Conventional methods for producing 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid have several industrial problems such as processability, environmental hazards, high cost, reagent reactivity, and necessary specialized equipment.

[0005] The present disclosure provides novel methods for preparing 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid and its derivatives. Compared with previous methods, the method benefits of the present disclosure are numerous and include improved overall yield, reduced cost, elimination of the need for mixed solvent separation, reduced waste, simplified operational complexity, and reduced process hazards.

[0006] The disclosed method provides an overall yield of about 50% using reagents that are commercially available and easy to handle. Summary of the invention

[0007] In one aspect, provided herein is a method for preparing a compound having formula VI, wherein

[0008]

[0009] R 5 -R 10 are each independently selected from hydrogen and halogen; and

[0010] R 13 is an organic acid, the method comprising:

[0011] I) forming a mixture comprising:

[0012] A) a compound of formula V, wherein

[0013]

[0014] R 5 -R 10are each independently selected from hydrogen and halogen;

[0015] R 12 is selected from the group consisting of ethers, esters and nitriles; and

[0016] Wherein the compound of formula V is prepared according to the following method, which comprises:

[0017] i) forming a mixture comprising:

[0018] a) a compound of formula III, wherein

[0019]

[0020] R 4 -R 10 are each independently selected from hydrogen and halogen; and wherein R 4 , R 5 and R 6 At least one of them is hydrogen;

[0021] b) a first solvent;

[0022] c) a second solvent;

[0023] d) compounds comprising metals; and

[0024] e) optionally additives; and

[0025] ii) reacting the mixture; and

[0026] B) a metal hydroxide; and

[0027] II) reacting the mixture.

[0028] In one aspect, provided herein is a method for preparing a compound having formula V, wherein

[0029]

[0030] R 5 -R 10 are each independently selected from hydrogen and halogen; and R 12 Selected from ethers, esters and nitriles, the method comprising:

[0031] I) forming a mixture comprising:

[0032] A) a compound of formula III, wherein

[0033]

[0034] R 4 is a halogen; and

[0035] R5 -R 10 are each independently selected from hydrogen and halogen;

[0036] B) a first solvent;

[0037] C) a second solvent;

[0038] D) a compound comprising a metal; and

[0039] E) optionally additives; and

[0040] II) reacting the mixture.

[0041] In one aspect, provided herein is a compound of formula V, wherein

[0042]

[0043] R 5 It is hydrogen;

[0044] R 6 and R 10 each independently a halogen;

[0045] R 7 -R 9 are each independently selected from hydrogen and halogen; and

[0046] R 12 It's nitrile.

[0047] In one aspect, provided herein is a method for preparing a compound having formula III, wherein

[0048]

[0049] R 4 -R 10 are each independently selected from hydrogen and halogen; and

[0050] Where R 4 , R 5 and R 6 At least one of the carbon atoms is hydrogen, the method comprising:

[0051] I) forming a mixture comprising:

[0052] A) a compound of formula II, wherein

[0053]

[0054] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen;

[0055] Where R 4 , R 5 and R 6 At least one of is hydrogen; and

[0056] Wherein the compound of formula II is prepared according to the following method, which comprises:

[0057] i) forming a mixture comprising:

[0058] a) a compound of formula I, wherein

[0059]

[0060] R 1 , R 2 and R 3 each independently a halogen;

[0061] b) optionally a dehalogenating agent;

[0062] c) a reducing agent; and

[0063] d) a solvent; and

[0064] ii) reacting the mixture;

[0065] B) a compound of formula IV, wherein

[0066]

[0067] R 7 -R 11 are each independently selected from hydrogen and halogen;

[0068] C) solvent;

[0069] D) an inorganic base; and

[0070] E) optionally additives; and

[0071] II) reacting the mixture.

[0072] In one aspect, provided herein is a method for preparing a compound having formula II, wherein

[0073]

[0074] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0075] Where R 4 , R 5 and R 6 At least one of the carbon atoms is hydrogen, the method comprising:

[0076] I) forming a mixture comprising

[0077] A) a compound of formula I, wherein

[0078]

[0079] R 1 , R 2 and R 3 are each independently a halogen; and

[0080] Wherein the compound of formula I is prepared according to the following method, which comprises:

[0081] i) forming a mixture comprising

[0082] a) pyrazole or a pyrazole derivative;

[0083] b) halogenating agent;

[0084] c) water;

[0085] d) optionally a solvent; and

[0086] e) optionally an inorganic base; and

[0087] ii) reacting the mixture;

[0088] B) optionally a dehalogenating agent;

[0089] C) a reducing agent; and

[0090] D) a solvent; and

[0091] II) reacting the mixture.

[0092] In one aspect, provided herein is a method for preparing a compound having formula VI, wherein

[0093]

[0094] R 5 -R 10 are each independently selected from hydrogen and halogen; and

[0095] R 13 is an organic acid, the method comprising:

[0096] I) forming a mixture comprising:

[0097] A) a compound of formula V, wherein

[0098]

[0099] R5 -R 10 are each independently selected from hydrogen and halogen;

[0100] R 12 is selected from the group consisting of ethers, esters and nitriles; and

[0101] Wherein the compound of formula V is prepared according to the following method, which comprises:

[0102] i) forming a mixture comprising:

[0103] a) a compound of formula III, wherein

[0104]

[0105] R 4 -R 10 are each independently selected from hydrogen and halogen; and wherein R 4 , R 5 and R 6 At least one of them is hydrogen;

[0106] b) cyanide reagent;

[0107] c) solvent;

[0108] d) compounds comprising metals; and

[0109] e) optionally additives; and

[0110] ii) reacting the mixture; and

[0111] B) acid; and

[0112] II) reacting the mixture.

[0113] In one aspect, provided herein is a method for preparing a compound having formula V, wherein

[0114]

[0115] R 5 -R 10 are each independently selected from hydrogen and halogen; and R 12 Selected from ethers, esters and nitriles, the method comprising:

[0116] I) forming a mixture comprising A) a compound of formula III, wherein

[0117]

[0118] R 4 is a halogen; and

[0119] R5 -R 10 each independently selected from hydrogen and halogen; B) a cyanide reagent;

[0120] C) a solvent;

[0121] D) a metal-containing compound; and

[0122] E) optionally an additive; and II) reacting the mixture.

[0123] In one aspect, the present invention provides a method for preparing a compound of formula II-A, wherein

[0124]

[0125] M is selected from alkali metals and alkaline earth metals;

[0126] R 4 、R 5 and R 6 each independently selected from hydrogen and halogen; and

[0127] wherein at least one of R 4 、R 5 and R 6 is hydrogen, the method comprising:

[0128] I) forming a mixture comprising:

[0129] A) a compound of formula I, wherein

[0130]

[0131] R 1 、R 2 and R 3 are each independently halogen; and

[0132] wherein the compound of formula I is prepared according to a method comprising:

[0133] i) forming a mixture comprising

[0134] a) pyrazole or a pyrazole derivative;

[0135] b) a halogenating reagent;

[0136] c) water;

[0137] d) optionally a solvent; and

[0138] e) optionally an inorganic base; and

[0139] ii) reacting the mixture;

[0140] B) optionally a dehalogenating agent;

[0141] C) a reducing agent; and

[0142] D) a solvent; and

[0143] II) reacting the mixture.

[0144] In one aspect, provided herein is a compound having formula II-A, wherein

[0145]

[0146] M is selected from alkali metals and alkaline earth metals;

[0147] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0148] Where R 4 , R 5 and R 6 At least one of them is hydrogen. DETAILED DESCRIPTION

[0149] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation otherwise expressly stated. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or other elements inherent to such composition, mixture, process, or method.

[0150] The transitional phrase "consisting of" excludes any unrecited element, step, or ingredient. If in a claim, such a phrase will render the claim closed-ended so that it does not include materials other than those recited, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the preamble, the phrase is limited only to the elements recited in that clause; other elements are not excluded from the claim as a whole.

[0151] The conjunction "consisting essentially of" is used to define compositions or methods that include materials, steps, features, components or elements other than those literally disclosed, provided that these additional materials, steps, features, components or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of" is intermediate between "comprising" and "consisting of."

[0152] When an invention or a portion thereof is defined by an open-ended term such as "comprising," it should be readily understood that (unless otherwise indicated) the description should be interpreted as also using the term "consisting essentially of" or "consisting of" to describe such an invention.

[0153] In addition, unless expressly stated to the contrary, "or" refers to an inclusive or rather than an exclusive or. For example, condition A or B is satisfied by any of the following conditions: 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 both A and B are true (or exist).

[0154] In addition, the indefinite article "a and an" before an element or component of the present invention is intended to be non-restrictive with respect to the number of instances (i.e., occurrences) of the element or component. Therefore, "a or an" should be understood to include one or at least one, and the singular word form of the element or component also includes the plural, unless the number obviously means the singular.

[0155] As used herein, the term "about" means plus or minus 10% of the value.

[0156] The term "halogen", alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. In addition, when used in compound words such as "haloalkyl", the alkyl group may be partially substituted or fully substituted by halogen atoms which may be the same or different.

[0157] When a group contains a substituent which may be hydrogen, for example R 4 When the substituent is regarded as hydrogen, this is considered to be equivalent to the group being unsubstituted.

[0158] The term "organic base" includes, but is not limited to, amine compounds (eg, primary, secondary, and tertiary amines), heterocycles including nitrogen-containing heterocycles, and ammonium hydroxide.

[0159] The term "inorganic base" includes, but is not limited to, inorganic compounds capable of reacting with or neutralizing an acid to form a salt, such as, for example, metal salts of hydroxides, carbonates, bicarbonates, and phosphates.

[0160] The term "halogenating agent" includes, but is not limited to, halogens and inorganic compounds such as, for example, bromine, NBS, and 1,3-dibromo-5,5-dimethylhydantoin.

[0161] The term "phase transfer catalyst" includes compounds that facilitate the migration of reactants from one phase to another phase where the reaction occurs. Phase transfer catalysis refers to the acceleration of a reaction after the addition of a phase transfer catalyst.

[0162] The term "ester" includes, but is not limited to, a functional group comprising an ester bond (C(=O)-O-). In some aspects, the functional group comprising an ester bond is an alkyl (or cycloalkyl) group having 1 to 8 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-methylheptyl (methylheptyl) (meptyl), etc.

[0163] The term "ether" includes, but is not limited to, functional groups containing an ether bond (COC).

[0164] The term "nitrile" includes, but is not limited to, functional groups containing a nitrile bond (-C≡N).

[0165] The term "carboxylic acid" includes, but is not limited to, functional groups containing a carboxylic acid bond (C(=O)-OH).

[0166] The term "organic acid" includes, but is not limited to, a functional group that imparts acidity and consists of atoms selected from the group consisting of carbon, nitrogen, oxygen and hydrogen.

[0167] Certain compounds of the present invention may exist as one or more stereoisomers.

[0168] 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 may exhibit beneficial effects when enriched relative to one or more other stereoisomers, or when separated from one or more other stereoisomers. In addition, those skilled in the art know how to separate, enrich and / or selectively prepare the stereoisomers.

[0169] Embodiments of the present disclosure include:

[0170] Example 1. A method for preparing a compound having formula VI, wherein

[0171]

[0172] R 5 -R 10 are each independently selected from hydrogen and halogen; and

[0173] R 13 is an organic acid, the method comprising:

[0174] I) forming a mixture comprising

[0175] A) a compound of formula V, wherein

[0176]

[0177] R 5 -R 10 are each independently selected from hydrogen and halogen;

[0178] R 12 is selected from the group consisting of ethers, esters and nitriles; and

[0179] Wherein the compound of formula V is prepared according to the following method, which comprises:

[0180] i) forming a mixture comprising:

[0181] a) a compound of formula III, wherein

[0182]

[0183] R 4 -R 10 are each independently selected from hydrogen and halogen; and wherein R 4 , R 5 and R 6 At least one of them is hydrogen;

[0184] b) a first solvent;

[0185] c) a second solvent;

[0186] d) compounds comprising metals; and

[0187] e) optionally additives; and

[0188] ii) reacting the mixture; and

[0189] B) a metal hydroxide; and

[0190] II) reacting the mixture.

[0191] Embodiment 2. The method as described in embodiment 1, wherein the metal hydroxide is selected from alkali metal hydroxides, alkaline earth metal hydroxides and combinations thereof.

[0192] Embodiment 3. The method as described in embodiment 2, wherein the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0193] Embodiment 4. The method as described in embodiment 2, wherein the alkaline earth metal hydroxide is selected from calcium hydroxide and barium hydroxide.

[0194] Embodiment 5. The method of embodiment 1, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 90°C.

[0195] Embodiment 6. The method of embodiment 1, wherein the metal-containing compound is selected from the group consisting of Grignard reagents and lithium-containing compounds.

[0196] Embodiment 7. The method of embodiment 6, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl and combinations thereof.

[0197] Embodiment 8. The method of embodiment 7, wherein the Grignard reagent is iPrMgBr.

[0198] Embodiment 9. The method of embodiment 6, wherein the lithium-containing compound is nBuLi.

[0199] Embodiment 10. The method of embodiment 1, wherein the first solvent is selected from THF, toluene, 1,4-dioxane, Me-THF and combinations thereof.

[0200] Embodiment 11. The method of embodiment 10, wherein the first solvent is THF.

[0201] Embodiment 12. The method of embodiment 1, wherein the second solvent is selected from dimethyl carbonate, N,N-dimethylacetamide and a combination thereof.

[0202] Embodiment 13. The method of embodiment 12, wherein the second solvent is dimethyl carbonate.

[0203] Embodiment 14. The method of embodiment 1, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 60°C.

[0204] Embodiment 15. The method of embodiment 14, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 30°C.

[0205] Embodiment 16. The method of embodiment 1, wherein R of formula III 4 , R 5 and R 6 are each independently hydrogen.

[0206] Embodiment 17. The method of embodiment 1, wherein the compound having the formula III is prepared according to the following method, which comprises:

[0207] I) forming a mixture comprising:

[0208] A) a compound of formula II, wherein

[0209]

[0210] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0211] Where R 4 , R 5 and R 6 At least one of them is hydrogen;

[0212] B) a compound of formula IV, wherein

[0213]

[0214] R 7 -R 11 are each independently selected from hydrogen and halogen;

[0215] C) solvent;

[0216] D) an inorganic base; and

[0217] E) optionally additives; and

[0218] II) reacting the mixture.

[0219] Embodiment 18. The method as described in 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 tert-butoxide and combinations thereof.

[0220] Embodiment 19. The method as described in Embodiment 17, wherein the solvent is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, NMP, cyclopentane, triethylene glycol dimethyl ether, diethylene glycol dimethyl ether and combinations thereof.

[0221] Embodiment 20. The method of embodiment 17, wherein the additive is selected from potassium iodide, a phase transfer catalyst and a combination thereof.

[0222] Embodiment 21. The method as described in embodiment 17, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6 and combinations thereof.

[0223] Embodiment 22. The method of embodiment 17, 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.

[0224] Embodiment 23. The method of embodiment 17, wherein the compound having the formula II is prepared according to the following method, which comprises:

[0225] I) forming a mixture comprising:

[0226] A) a compound of formula I, wherein

[0227]

[0228] R 1 , R 2 and R 3 each independently a halogen;

[0229] B) optionally a dehalogenating agent;

[0230] C) a reducing agent; and

[0231] D) a solvent; and

[0232] II) reacting the mixture.

[0233] Embodiment 24. A method as described in Embodiment 23, wherein the solvent is selected from acetic acid, water, toluene, p-dichlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, cyclopentane, N-methyl-2-pyrrolidone (NMP) and combinations thereof.

[0234] Embodiment 25. The method as described in Embodiment 23, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate and combinations thereof.

[0235] Embodiment 26. The method as described in Embodiment 23, wherein the dehalogenation agent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide and combinations thereof.

[0236] Embodiment 27. The method of embodiment 23, 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.

[0237] Embodiment 28. The method of embodiment 23, wherein the compound of formula I is prepared according to the following method, which comprises:

[0238] I) forming a mixture comprising

[0239] A) pyrazole or pyrazole derivatives;

[0240] B) halogenating agent;

[0241] C) water; and

[0242] D) optionally a solvent; and

[0243] E) optionally an inorganic base; and

[0244] II) reacting the mixture.

[0245] Embodiment 29. The method of embodiment 28, wherein the halogenation reagent comprises:

[0246] A) a reagent selected from the group consisting of hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and

[0247] B) Optionally hydrogen peroxide.

[0248] 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.

[0249] Embodiment 31. The method of embodiment 28, 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.

[0250] Example 32. A method for preparing a compound having formula V, wherein

[0251]

[0252] R 5 -R 10 are each independently selected from hydrogen and halogen; and

[0253] R 12 Selected from ethers, esters and nitriles, the method comprising:

[0254] I) forming a mixture comprising

[0255] A) a compound of formula III, wherein

[0256]

[0257] R 4 is a halogen; and

[0258] R 5 -R 10 are each independently selected from hydrogen and halogen;

[0259] B) a first solvent;

[0260] C) a second solvent;

[0261] D) a compound comprising a metal; and

[0262] E) optionally additives; and

[0263] II) reacting the mixture.

[0264] Embodiment 33. The method of embodiment 32, wherein the metal-containing compound is selected from Grignard reagents and lithium-containing compounds.

[0265] Embodiment 34. The method of embodiment 33, wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl and combinations thereof.

[0266] Embodiment 35. The method of embodiment 34, wherein the Grignard reagent is iPrMgBr.

[0267] Embodiment 36. The method of embodiment 33, wherein the lithium-containing compound is nBuLi.

[0268] Embodiment 37. The method of embodiment 32, wherein the first solvent is selected from THF, toluene, 1,4-dioxane, Me-THF and combinations thereof.

[0269] Embodiment 38. The method of embodiment 37, wherein the first solvent is THF.

[0270] Embodiment 39. The method of embodiment 32, wherein the second solvent is selected from dimethyl carbonate, N,N-dimethylacetamide and a combination thereof.

[0271] Embodiment 40. The method of embodiment 39, wherein the second solvent is dimethyl carbonate.

[0272] Embodiment 41. The method of embodiment 32, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 60°C.

[0273] Embodiment 42. The method of embodiment 41, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 30°C.

[0274] Embodiment 43. The method of embodiment 32, wherein R of formula III 4 , R 5 and R 6 are each independently hydrogen.

[0275] Embodiment 44. A compound having formula V, wherein

[0276]

[0277] R 5 It is hydrogen;

[0278] R 6and R 10 each independently a halogen;

[0279] R 7 -R 9 are each independently selected from hydrogen and halogen; and

[0280] R 12 It's nitrile.

[0281] Embodiment 45. The compound as described in Embodiment 44, wherein the compound is

[0282]

[0283] Example 46. A method for preparing a compound having formula III, wherein

[0284]

[0285] R 4 -R 10 are each independently selected from hydrogen and halogen; and

[0286] Where R 4 , R 5 and R 6 At least one of the components is hydrogen, the method comprising: 1) forming a mixture comprising:

[0287] A) a compound of formula II, wherein

[0288]

[0289] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen;

[0290] Where R 4 , R 5 and R 6 At least one of is hydrogen; and

[0291] Wherein the compound of formula II is prepared according to the following method, which comprises:

[0292] i) forming a mixture comprising:

[0293] a) a compound of formula I, wherein

[0294]

[0295] R 1 , R 2 and R 3 each independently a halogen;

[0296] b) optionally a dehalogenating agent;

[0297] c) a reducing agent; and

[0298] d) a solvent; and

[0299] ii) reacting the mixture;

[0300] B) a compound of formula IV, wherein

[0301]

[0302] R 7 -R 11 are each independently selected from hydrogen and halogen;

[0303] C) solvent;

[0304] D) an inorganic base; and

[0305] E) optionally additives; and

[0306] II) reacting the mixture.

[0307] Embodiment 47. The method as described in 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 tert-butoxide and combinations thereof.

[0308] Embodiment 48. The method as described in Embodiment 46, wherein the solvent C) is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, NMP, cyclopentane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and combinations thereof.

[0309] Embodiment 49. The method as described in Embodiment 46, wherein the additive is selected from potassium iodide, a phase transfer catalyst and a combination thereof.

[0310] Embodiment 50. The method as described in Embodiment 49, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6 and combinations thereof.

[0311] 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.

[0312] 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.

[0313] Embodiment 53. A method as described in Embodiment 46, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate and combinations thereof.

[0314] Embodiment 54. The method as described in Embodiment 46, wherein the dehalogenation reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide and combinations thereof.

[0315] Embodiment 55. The method of embodiment 46, 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.

[0316] Embodiment 56. The method of embodiment 46, wherein the compound of formula I is prepared according to the following method, which comprises:

[0317] I) forming a mixture comprising

[0318] A) pyrazole or pyrazole derivatives;

[0319] B) halogenating agent;

[0320] C) water; and

[0321] D) optionally a solvent; and

[0322] E) optionally an inorganic base; and

[0323] II) reacting the mixture.

[0324] Embodiment 57. The method of embodiment 56, wherein the halogenation reagent comprises:

[0325] A) a reagent selected from the group consisting of hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and

[0326] B) Optionally hydrogen peroxide.

[0327] 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.

[0328] Embodiment 59. The method of embodiment 56, 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.

[0329] Embodiment 60. A method for preparing a compound having formula II, wherein

[0330]

[0331] R4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0332] Where R 4 , R 5 and R 6 At least one of the carbon atoms is hydrogen, the method comprising:

[0333] I) forming a mixture comprising:

[0334] A) a compound of formula I, wherein

[0335]

[0336] R 1 , R 2 and R 3 are each independently a halogen; and

[0337] Wherein the compound of formula I is prepared according to the following method, which comprises:

[0338] i) forming a mixture comprising:

[0339] a) pyrazole or a pyrazole derivative;

[0340] b) halogenating agent;

[0341] c) water; and

[0342] d) optionally a solvent; and

[0343] e) optionally an inorganic base; and

[0344] ii) reacting the mixture;

[0345] B) optionally a dehalogenating agent;

[0346] C) a reducing agent; and

[0347] D) a solvent; and

[0348] II) reacting the mixture.

[0349] Embodiment 61-I. The method as described in embodiment 60, wherein the solvent d) is selected from alkanes, ethers, halogenated solvents, esters, water and combinations thereof. In some embodiments, the halogenated solvent is selected from dichloromethane, chloromethane, 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.

[0350] Example 61-II. The method as described in Example 60, wherein the solvent D) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and combinations thereof.

[0351] Embodiment 62. A method as described in Embodiment 60, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate and combinations thereof.

[0352] Embodiment 63. The method as described in Embodiment 60, wherein the dehalogenation reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide and combinations thereof.

[0353] 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.

[0354] Embodiment 65. The method of embodiment 60, wherein the halogenation reagent comprises:

[0355] A) a reagent selected from the group consisting of hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and

[0356] B) Optionally hydrogen peroxide.

[0357] 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.

[0358] Embodiment 67. The method of embodiment 60, 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.

[0359] Embodiment 68. A method for preparing a compound having formula VI, wherein

[0360]

[0361] R 5 -R 10 are each independently selected from hydrogen and halogen; and

[0362] R 13 is an organic acid, the method comprising:

[0363] I) forming a mixture comprising:

[0364] A) a compound of formula V, wherein

[0365]

[0366] R5 -R 10 are each independently selected from hydrogen and halogen;

[0367] R 12 is selected from the group consisting of ethers, esters and nitriles; and

[0368] Wherein the compound of formula V is prepared according to the following method, which comprises:

[0369] i) forming a mixture comprising:

[0370] a) a compound of formula III, wherein

[0371]

[0372] R 4 -R 10 are each independently selected from hydrogen and halogen; and wherein R 4 , R 5 and R 6 At least one of them is hydrogen;

[0373] b) cyanide reagent;

[0374] c) solvent;

[0375] d) compounds comprising metals; and

[0376] e) optionally additives; and

[0377] ii) reacting the mixture; and

[0378] B) acid; and

[0379] II) reacting the mixture.

[0380] Embodiment 69. The method of embodiment 68, wherein the acid is selected from H 2 SO 4 , HCl and combinations thereof.

[0381] 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.

[0382] Embodiment 71. The method of Embodiment 68, wherein the metal-containing compound is a transition metal catalyst.

[0383] Embodiment 72. The method of embodiment 71, wherein the transition metal catalyst is cuprous iodide.

[0384] Embodiment 73. The method as described in Embodiment 68, wherein the cyanide reagent is selected from sodium cyanide, copper (I) cyanide, zinc cyanide and combinations thereof.

[0385] Embodiment 74. The method of embodiment 73, wherein the cyanation reagent is sodium cyanide.

[0386] Embodiment 75. A method as described in Embodiment 68, wherein the solvent is selected from N-methyl-2-pyrrolidone (NMP), acetonitrile, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, ethylene glycol, propylene glycol, ethanol, isobutyl alcohol, and alcohol and cyclopentane sulfone, dimethyl carbonate, N,N-dimethylacetamide and combinations thereof.

[0387] Embodiment 76. The method of embodiment 75, wherein the solvent is N,N-dimethylacetamide or diethylene glycol dimethyl ether.

[0388] Embodiment 77. The method of embodiment 68, 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.

[0389] Embodiment 78. The method of embodiment 77, 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.

[0390] Embodiment 79. The method as described in Embodiment 68, wherein the additive is selected from potassium iodide, a phase transfer catalyst and a combination thereof.

[0391] Embodiment 80. The method of embodiment 79, wherein the additive is potassium iodide.

[0392] Embodiment 81. The method of embodiment 68, wherein R of formula III 4 , R 5 and R 6 are each independently hydrogen.

[0393] Embodiment 82. The method of embodiment 68, wherein the compound of formula III is prepared according to the following method, the method comprising:

[0394] I) forming a mixture comprising:

[0395] A) a compound of formula II, wherein

[0396]

[0397] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0398] Where R 4 , R 5 and R 6 At least one of them is hydrogen;

[0399] B) a compound of formula IV, wherein

[0400]

[0401] R 7 -R 11 are each independently selected from hydrogen and halogen;

[0402] C) solvent;

[0403] D) an inorganic base; and

[0404] E) optionally additives; and

[0405] II) reacting the mixture.

[0406] Embodiment 83. The method as described in Embodiment 82, wherein 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.

[0407] Embodiment 84. The method as described in Embodiment 82, wherein the solvent is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and combinations thereof.

[0408] Embodiment 85. The method as described in Embodiment 82, wherein the additive is selected from potassium iodide, a phase transfer catalyst and a combination thereof.

[0409] Embodiment 86. The method as described in Embodiment 85, wherein the phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6 and combinations thereof.

[0410] 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.

[0411] Embodiment 88. The method of embodiment 82, wherein the compound of formula II is prepared according to the following method, the method comprising:

[0412] I) forming a mixture comprising:

[0413] A) a compound of formula I, wherein

[0414]

[0415] R 1 , R2 and R 3 each independently a halogen;

[0416] B) optionally a dehalogenating agent;

[0417] C) a reducing agent; and

[0418] D) a solvent; and

[0419] II) reacting the mixture.

[0420] Embodiment 89. The method as described in Embodiment 88, wherein the solvent is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and combinations thereof.

[0421] Embodiment 90. A method as described in Embodiment 88, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate and combinations thereof.

[0422] Embodiment 91. The method as described in Embodiment 88, wherein the dehalogenation reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide and combinations thereof.

[0423] 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.

[0424] Embodiment 93. The method of embodiment 88, wherein the compound of formula I is prepared according to the following method, comprising:

[0425] I) forming a mixture comprising:

[0426] A) pyrazole or pyrazole derivatives;

[0427] B) halogenating agent;

[0428] C) water; and

[0429] D) optionally a solvent; and

[0430] E) optionally an inorganic base; and

[0431] II) reacting the mixture.

[0432] Embodiment 94. The method of embodiment 93, wherein the halogenating agent comprises:

[0433] A) a reagent selected from the group consisting of hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and

[0434] B) Optionally hydrogen peroxide.

[0435] Embodiment 95. The method as described in Embodiment 93, wherein the inorganic base is selected from powdered sodium hydroxide, sodium hydroxide solution, powdered sodium acetate and combinations thereof.

[0436] Embodiment 95-I. The method as described in embodiment 93, wherein the solvent is selected from alkanes, ethers, halogenated solvents, esters, water and combinations thereof. In some embodiments, the halogenated solvent is selected from dichloromethane, chloromethane, 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.

[0437] 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.

[0438] Embodiment 97. A method for preparing a compound having formula V, wherein

[0439]

[0440] R 5 -R 10 are each independently selected from hydrogen and halogen; and

[0441] R 12 Selected from ethers, esters and nitriles, the method comprising:

[0442] I) forming a mixture comprising:

[0443] A) a compound of formula III, wherein

[0444]

[0445] R 4 is a halogen; and

[0446] R 5 -R 10 are each independently selected from hydrogen and halogen;

[0447] B) Cyanide reagent;

[0448] C) solvent;

[0449] D) a compound comprising a metal; and

[0450] E) optionally additives; and

[0451] II) reacting the mixture.

[0452] Embodiment 98. The method of Embodiment 97, wherein the metal-containing compound is a transition metal catalyst.

[0453] Embodiment 99. The method as described in Embodiment 98, wherein the transition metal catalyst is selected from cuprous iodide, cuprous bromide, cuprous oxide and combinations thereof.

[0454] Embodiment 100. The method of Embodiment 99, wherein the transition metal catalyst is cuprous iodide.

[0455] Embodiment 101. A method as described in Embodiment 97, wherein the cyanide reagent is selected from sodium cyanide, copper (I) cyanide, zinc cyanide and combinations thereof.

[0456] Embodiment 102. The method of embodiment 101, wherein the cyanation reagent is sodium cyanide.

[0457] Embodiment 103. A method as described in Embodiment 97, wherein the solvent is selected from N-methyl-2-pyrrolidone (NMP), acetonitrile, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, ethylene glycol, propylene glycol, ethanol, isobutyl alcohol, and alcohol and cyclopentane sulfone, dimethyl carbonate, N,N-dimethylacetamide and combinations thereof.

[0458] Embodiment 104. The method of embodiment 103, wherein the solvent is N,N-dimethylacetamide or diglyme.

[0459] 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.

[0460] 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.

[0461] Embodiment 107. The method as described in Embodiment 97, wherein the additive is selected from potassium iodide, a phase transfer catalyst and a combination thereof.

[0462] Embodiment 108. The method of embodiment 107, wherein the additive is potassium iodide.

[0463] Embodiment 109. The method of embodiment 97, wherein R of formula III 4 , R 5 and R 6 are each independently hydrogen.

[0464] Embodiment 110. A method for preparing a compound having formula II-A, wherein

[0465]

[0466] M is selected from alkali metals and alkaline earth metals;

[0467] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0468] Where R 4 , R 5 and R 6 At least one of the carbon atoms is hydrogen, the method comprising:

[0469] I) forming a mixture comprising:

[0470] A) a compound of formula I, wherein

[0471]

[0472] R 1 , R 2 and R 3 are each independently a halogen; and

[0473] Wherein the compound of formula I is prepared according to the following method, which comprises:

[0474] i) forming a mixture comprising

[0475] a) pyrazole or a pyrazole derivative;

[0476] b) halogenating agent;

[0477] c) water; and

[0478] d) optionally an inorganic base; and

[0479] ii) reacting the mixture;

[0480] B) optionally a dehalogenating agent;

[0481] C) a reducing agent; and

[0482] D) a solvent; and

[0483] II) reacting the mixture.

[0484] Embodiment 111-I. The method as described in embodiment 60, wherein the solvent d) is selected from alkanes, ethers, halogenated solvents, esters, water and combinations thereof. In some embodiments, the halogenated solvent is selected from dichloromethane, chloromethane, 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.

[0485] Embodiment 111-II. The method as described in Embodiment 110, wherein the solvent D) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and combinations thereof.

[0486] Embodiment 112. A method as described in Embodiment 110, wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate and combinations thereof.

[0487] Embodiment 113. The method as described in Embodiment 110, wherein the dehalogenation reagent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide and combinations thereof.

[0488] 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.

[0489] Embodiment 115. The method of embodiment 110, wherein the halogenation reagent comprises:

[0490] A) a reagent selected from the group consisting of hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and

[0491] B) Optionally hydrogen peroxide.

[0492] 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.

[0493] Embodiment 117. The method of embodiment 110, 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.

[0494] Embodiment 118. The method of embodiment 110, wherein M is selected from lithium, sodium, potassium, calcium and magnesium.

[0495] Embodiment 119. The method of embodiment 110, wherein the compound of formula II-A is

[0496]

[0497] Embodiment 120. A compound having formula II-A, wherein

[0498]

[0499] M is selected from alkali metals and alkaline earth metals;

[0500] R 4 , R 5 and R 6 are each independently selected from hydrogen and halogen; and

[0501] Where R 4 , R 5 and R 6 At least one of them is hydrogen.

[0502] Embodiment 121. The compound as described in Embodiment 120, wherein the compound is

[0503]

[0504] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 1. The R group is as defined anywhere in the disclosure.

[0505] Solution 1.

[0506]

[0507] In one aspect, 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid is prepared according to the method represented by Scheme 2.

[0508] Solution 2.

[0509]

[0510] In one aspect, 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid is prepared according to the method represented by Scheme 3.

[0511] Solution 3.

[0512]

[0513] In one aspect, compounds having Formula I are prepared according to the method represented by Scheme 4. The R group is as defined anywhere in the disclosure.

[0514] Solution 4.

[0515]

[0516] This aspect comprises reacting pyrazole with a halogenating agent in water and optionally a solvent and further optionally in the presence of an inorganic base. In one embodiment, the halogenating agent is selected from hydrogen peroxide / HBr, bromine (Br 2 ), N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, hydrogen peroxide / NaBr, hydrogen peroxide / KBr, hydrogen peroxide / Br 2 and combinations thereof. In another embodiment, the halogenating agent 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, there is no base. In one embodiment, the reaction temperature is in the range of from about 0°C to about 70°C. In another embodiment, the reaction temperature is in the range of from 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.

[0517] In one aspect, compounds having Formula II are prepared according to the method represented by Scheme 5. The R group is as defined anywhere in the disclosure.

[0518] Solution 5.

[0519]

[0520] This aspect includes reacting a compound having formula I with a dehalogenating agent 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 dehalogenating agent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide (TBAI), and combinations thereof. In another embodiment, the dehalogenating agent is potassium iodide. In one embodiment, the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, 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 from about 100°C to about 180°C. In another embodiment, the reaction temperature is in the range of from about 160°C to about 180°C.

[0521] In one aspect, compounds having Formula II-A are prepared according to the method represented by Scheme 6. The R group is as defined anywhere in the disclosure.

[0522] Solution 6.

[0523]

[0524] 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 potassium. In another embodiment, M is selected from calcium and magnesium.

[0525] In one embodiment, the compound having Formula II-A is:

[0526]

[0527] This aspect includes reacting a compound having formula I with a dehalogenating agent 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 dehalogenating agent is selected from sodium iodide, iodine, potassium iodide, tetra-n-butylammonium iodide (TBAI), and combinations thereof. In another embodiment, the dehalogenating agent is potassium iodide. In one embodiment, the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium dithionite, 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 from about 100°C to about 180°C. In another embodiment, the reaction temperature is in the range of from about 160°C to about 180°C.

[0528] In one aspect, compounds having Formula III are prepared according to the method represented by Scheme 7. The R group is as defined anywhere in the disclosure.

[0529] Solution 7.

[0530]

[0531] This aspect includes the step of mixing a compound of formula II with a compound of formula IV in a solvent in the presence of an inorganic base and optionally an additive. 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 tert-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), cyclopentane, diglyme, triglyme, and combinations thereof. In another embodiment, the solvent is N,N-dimethylacetamide (DMAc). In yet another embodiment, the solvent is cyclopentane. In one embodiment, the additive is a phase catalyst selected from butylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), aliquat-336, 18-crown-6, and combinations thereof. In another embodiment, the phase catalyst is 18-crown-6. In another embodiment, the additive is potassium iodide. In one embodiment, the reaction temperature is in a range from about 140°C to about 200°C. In another embodiment, the temperature is in a range from about 155°C to about 175°C.

[0532] In one aspect, compounds having Formula V are prepared according to the method represented by Scheme 8. The R group is as defined anywhere in the disclosure.

[0533] Solution 8.

[0534]

[0535] This aspect includes mixing a compound of formula III with dimethyl carbonate (DMC) in a solvent in the presence of an alkali agent and optionally an additive. In one embodiment, the alkali agent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, nBuLi and combinations thereof. In another embodiment, the alkali agent 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 from about 0°C to about 60°C. In another embodiment, the temperature is in the range of from about 0°C to about 30°C.

[0536] In one aspect, compounds having Formula V are prepared according to the method represented by Scheme 9. The R group is as defined anywhere in the disclosure.

[0537] Solution 9.

[0538]

[0539] This aspect includes mixing a 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 and 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 from about 120°C to about 150°C. In another embodiment, the reaction temperature is in the range of from about 130°C to about 140°C.

[0540] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 10. The R group is as defined anywhere in the disclosure.

[0541] Solution 10.

[0542]

[0543] This aspect includes reacting a compound of formula V with an aqueous metal hydroxide solution. In one embodiment, the metal hydroxide is selected from alkali metal hydroxides, alkaline earth metal hydroxides, 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 reaction temperature is in the range of from about 0°C to about 90°C. In another embodiment, the reaction temperature is in the range of from about 60°C to about 80°C.

[0544] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 11. The R group is as defined anywhere in the disclosure.

[0545] Solution 11.

[0546]

[0547] 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 H 2 SO 4 , HCl and combinations thereof. In another embodiment, the acid is H2 SO 4 In one embodiment, the reaction temperature is in the range of from about 50°C to about 100°C. In another embodiment, the reaction temperature is in the range of from about 75°C to about 85°C.

[0548] Examples

[0549] Without further elaboration, it is believed that those skilled in the art can make the most of the present invention using the previous description. Therefore, the following examples should be interpreted as being illustrative only and not limiting the present disclosure in any way. The starting materials of the following examples may not necessarily be prepared by specific preparation runs, and their procedures are described in other embodiments. It should also be understood that any numerical ranges listed herein include all values ​​from the lower limit to the upper limit. For example, if the range is specified as 10-50, it is expected that values ​​such as 12-30, 20-40 or 30-50 are explicitly listed in this specification. These are only examples of special expectations, and all possible combinations of numerical values ​​between the lowest and highest values ​​listed (and including the lowest and highest values) will be considered to be clearly stated in this application.

[0550] Example 1. Hydrogen peroxide / HBr as halogenating agent.

[0551] 34 g of pyrazole and 505.8 g of 48% hydrogen bromide solution were charged into a reactor. 170 g of 30% hydrogen peroxide was added dropwise at 0° C. over 2 hours. The reaction temperature was controlled at 0° C.-30° C. After the reaction, the product was precipitated as a solid, and then the reaction mixture was quenched with 10% sodium sulfite. After filtration and drying, 142 g of high purity (95%, LC area) 3,4,5-tribromo-1H-pyrazole was obtained.

[0552] Example 2. Bromine / sodium hydroxide as halogenating agent.

[0553] 34 g of pyrazole was dissolved in water, and then sodium hydroxide was added at 0°C to obtain the corresponding pyrazole sodium salt. Next, 239.7 g of bromine was added dropwise at 0°C over 2 hours. The reaction temperature was controlled at 20°C-40°C. After the reaction, the product was precipitated as a solid, and then the reaction mixture was quenched with 10% sodium sulfite. After filtration and drying, 147 g of high purity (98%, LC area) 3,4,5-tribromo-1H-pyrazole was obtained.

[0554] Example 3. Potassium iodide / sodium sulfite as dehalogenation reagent.

[0555] 100 g of 3,4,5-tribromo-1H-pyrazole, 1.1 g of KI and 62 g of Na 2 SO 3The reaction was carried out at 160°C-180°C for 5 hours to complete the reaction. After the reaction was completed, the reaction mixture was filtered, and then DMAc was distilled out under vacuum. Next, water was added to the crude product. The reaction mixture was stirred for 10 min. The product 3,5-dibromo-1H-pyrazole was precipitated as a solid. After filtration and drying, 68 g of high purity (98%, LC area) 3,5-dibromo-1H-pyrazole was obtained.

[0556] Example 4. Coupling reaction.

[0557] 22.6 grams of 3,5-dibromo-1H-pyrazole and 4.2 g of NaOH are reacted at a temperature of 150°C-160°C in the presence of toluene. Water is removed by azeotropic distillation at reflux temperature to produce the corresponding 3,5-dibromo-1H-pyrazole sodium salt. Then, DMAc and 15.5 g of 2,3-dichloropyridine are added, and the mixture is reacted in an autoclave at 150°C-170°C to produce 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine. After the reaction, the reaction mixture is filtered. The DMAc solution containing 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine can be used in subsequent steps.

[0558] Example 5. Reactions in the presence of transition metal catalysts.

[0559] At 10 ℃-25 ℃, 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. Next, the reaction mixture was stirred at 130 ℃-140 ℃ for 6 hours to complete the reaction. DMAc was distilled out under vacuum. Toluene was added and stirred for 30 minutes. Next, the solution was filtered and 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 were obtained.

[0560] Example 6. Acidification.

[0561] 28.4 g of high purity (94%, LC area) 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonitrile was dissolved in 50% H 2 SO 4 The solution was added and placed in a flask. The mixture was heated to 80°C-85°C and maintained 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 a NaOH solution to precipitate the corresponding 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid sodium salt. H 2 SO 4The pH was adjusted to a value in the range of about 1 to about 2 to precipitate 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.

[0562] Example 7. Reaction in the presence of a Grignard reagent.

[0563] 33.7 grams of 3-chloro-2-(3,5-dibromo-1H-pyrazol-1-yl)pyridine were dissolved in THF, and then iPrMgCl was added at 0°C to produce 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°C-40°C. After the reaction, THF and DMC were distilled off under reduced pressure, and the reaction mixture was then quenched with water. Next, toluene was added. After separation and concentration, 33 g of high purity (90%, EC area) 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester was obtained.

[0564] Example 8. Hydrolysis.

[0565] 33 g of high purity (90%, LC area) 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester, 12 g of 33% NaOH solution and 90 g of toluene were charged into a flask, and the mixture was heated to 80° C.-85° C. and maintained at this temperature for 1-2 hours to complete the reaction. 2 SO 4 The pH is adjusted to a value in the range of about 1 to about 2 to precipitate 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid.

[0566] This written description 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 with insubstantial differences from the literal language of the claims.

Claims

1. A method for preparing a compound of formula VI, in, R 5 It is hydrogen; R 6 It is a halogen; R 7 -R 10 are each independently selected from hydrogen and halogen; and R 13 is a carboxyl group, the method comprising: I) forming a mixture comprising: A) a compound of formula V, wherein R 5 It is hydrogen; R 6 It is a halogen; R 7 -R 10 are each independently selected from hydrogen and halogen; R 12 is an ester group; and Wherein the compound of formula V is prepared according to the following method, which comprises: i) forming a mixture comprising: a) a compound of formula III, wherein R 4 and R 6 is a halogen, R 5 is hydrogen, and R 7 -R 10 are each independently selected from hydrogen and halogen; b) a first solvent; c) dimethyl carbonate; and d) iPrMgCl; and ii) reacting the mixture at a reaction temperature in the range of 20°C to 40°C; and B) a metal hydroxide; and II) reacting the mixture.

2. The method according to claim 1, in, The metal hydroxide is selected from alkali metal hydroxides, alkaline earth metal hydroxides and combinations thereof.

3. The method according to claim 1, in, The first solvent is selected from THF, toluene, 1,4-dioxane, Me-THF and combinations thereof.

4. The method according to claim 1, in, The compound of formula III is prepared according to the following method, which comprises: I) forming a mixture comprising: A) a compound of formula II, wherein R 4 and R 6 is a halogen, and R 5 It is hydrogen; B) a compound of 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 selected from the group consisting of potassium iodide, a phase transfer catalyst, and combinations thereof; and II) reacting the mixture.

5. The method according to claim 4, in, The inorganic base is selected from powdered sodium hydroxide, powdered potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, powdered sodium methoxide, powdered potassium tert-butoxide and combinations thereof.

6. The method according to claim 4, in, The solvent is selected from toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), sulfolane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and a combination thereof.

7. The method according to claim 4, in, The phase transfer catalyst is selected from butylammonium chloride, tetrabutylammonium bromide, aliquat-336, 18-crown-6 and a combination thereof.

8. The method according to claim 4, in, Process step II) of reacting the mixture takes place at a reaction temperature in the range from 140°C to 200°C.

9. The method according to claim 4, in, The compound of formula II is prepared according to the following method, which comprises: I) forming a mixture comprising: A) a compound of formula I, wherein R 1 , R 2 and R 3 each independently a halogen; B) optionally a dehalogenating agent; C) a reducing agent; and D) a solvent; and II) reacting the mixture.

10. The method according to claim 9, in, The solvent is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and a combination thereof.

11. The method according to claim 9, in, The compound of formula I is prepared according to the following method, which comprises: I) forming a mixture comprising: A) pyrazole or pyrazole derivatives; B) halogenating agent; C) Water; D) optionally a solvent; and E) optionally an inorganic base; and II) reacting the mixture.

12. The method according to claim 11, in, The halogenating agent comprises: A) a reagent selected from the group consisting of hydrogen bromide, bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, sodium bromide, potassium bromide, and combinations thereof; and B) Optionally hydrogen peroxide.

13. A method for preparing a compound of formula V, in, R 5 It is hydrogen; R 6 It is a halogen; R 7 -R 10 are each independently selected from hydrogen and halogen; and R 12 is an ester group, the method comprising: I) forming a mixture comprising: A) a compound of formula III, wherein R 4 and R 6 It is a halogen; R 5 is hydrogen; and R 7 -R 10 are each independently selected from hydrogen and halogen; B) a first solvent; C) dimethyl carbonate; and D) iPrMgCl; and II) reacting the mixture at a reaction temperature in the range of 20°C to 40°C.

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