Process for the preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate

Abstract

Described herein is a method for synthesizing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,772, filed January 31, 2022.

[0002] The present disclosure is directed to a method for synthesizing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate. Compounds prepared by the methods disclosed herein are particularly useful in the preparation of certain anthranilamide compounds of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole. [Background technology]

[0003] The present disclosure provides a novel method useful for preparing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate and its derivatives. Methods for preparing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate are known in the art, such as those described in WO 2004 / 087689. However, these known methods are expensive and wasteful.

[0004] Compared to conventional processes, the advantages of the disclosed method are numerous, including improved waste reduction, increased flexibility in brominating reagent selection, reduced brominating agent usage, increased yields, and reduced costs. Summary of the Invention [Means for solving the problem]

[0005] In one embodiment, there is provided a method for preparing a compound of formula (II) comprising: [ka] (In the formula, R 5 is a halogen; Each R 6 are independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C3-C6 (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, or C3-C6 trialkylsilyl; R 7 is H or C1-C4 alkyl; Y is N or CR 8 and; R 8 is H or R 6 and m is 0, 1, 2, or 3, with the proviso that when X is CH, m is at least 1. I) forming a mixture comprising: A) A compound of formula (I) [ka] (In the formula, R 1 is a sulfonate; Each R 2are independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C3-C6 (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, or C3-C6 trialkylsilyl; R 3 is H or C1-C4 alkyl; X is N or CR 4 and; R 4 is H or R 2 and n is 0, 1, 2, or 3, with the proviso that when X is CH, then n is at least 1; B) a solvent; and C) optionally bromide; II) introducing a brominating agent into the mixture; III) introducing a strong acid into the mixture; and IV) Optionally adding a base to the mixture. Provided herein is a method comprising: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Described herein is a method for synthesizing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate.

[0007] Embodiments of the present disclosure include:

[0008] Embodiment 1. A method for preparing a compound of formula (II) comprising: [ka] (In the formula, R 5 is a halogen; Each R 6 are independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C3-C6 (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, or C3-C6 trialkylsilyl; R 7 is H or C1-C4 alkyl; Y is N or CR 8 and; R 8 is H or R 6 and m is 0, 1, 2, or 3, with the proviso that when X is CH, m is at least 1. I) forming a mixture comprising: A) A compound of formula (I) [ka] (In the formula, R 1 is a sulfonate; Each R 2are independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C3-C6 (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, or C3-C6 trialkylsilyl; R 3 is H or C1-C4 alkyl; X is N or CR 4 and; R 4 is H or R 2 and n is 0, 1, 2, or 3, with the proviso that when X is CH, then n is at least 1; B) a solvent; and C) optionally bromide; II) introducing a brominating agent into the mixture; III) introducing a strong acid into the mixture; and IV) Optionally adding a base to the mixture. The method includes:

[0009] The method of embodiment 1, wherein m is 1, 2, or 3.

[0010] Embodiment 3.R 5 The method of embodiment 1 or 2, wherein is Cl or Br.

[0011] Embodiment 4.R 6 The method of any one of embodiments 1-3, wherein is independently Cl or Br.

[0012] Embodiment 5. One R 6The method of any one of embodiments 1 to 4, wherein:

[0013] Embodiment 6.R 7 The method of any one of embodiments 1 to 5, wherein is C1 to C4 alkyl.

[0014] Embodiment 7. The method of any one of embodiments 1-6, wherein Y is N.

[0015] Embodiment 8. The method of any one of embodiments 1-7, wherein the compound of formula (II) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate, having the following structure: [ka]

[0016] Embodiment 9. The method of any one of embodiments 1 to 8, wherein n is 1, 2, or 3.

[0017] Embodiment 10.R 1 The method of any one of embodiments 1-9, wherein is selected from methanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0018] Embodiment 11.R 2 The method of any one of embodiments 1-10, wherein is independently Cl or Br.

[0019] Embodiment 12. One R 2 The method of any one of embodiments 1 to 11, wherein:

[0020] Embodiment 13.R 3 The method of any one of embodiments 1 to 12, wherein is C1-C4 alkyl.

[0021] Embodiment 14. The method of any one of embodiments 1 to 13, wherein X is N.

[0022] Embodiment 15. The method of any one of embodiments 1-14, wherein the compound of formula (I) is ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate, having the following structure: [ka]

[0023] Embodiment 16. The method of any one of embodiments 1-15, wherein the solvent is selected from dibromomethane, dichloromethane, acetic acid, ethyl acetate, acetonitrile, dichloroethane, dibromoethane, and combinations thereof.

[0024] Embodiment 17. The method of any one of embodiments 1-16, wherein the solvent comprises acetic acid in an amount ranging from about 0.1 equivalents to about 10 equivalents, preferably from about 0.5 equivalents to about 6 equivalents.

[0025] Embodiment 18. The method of any one of embodiments 1-17, wherein the bromide is selected from phosphorus oxybromide, phosphorus pentabromide, phosphorus tribromide, dibromotrialkylphosphines and dibromodiphenylphosphines, and combinations thereof.

[0026] Embodiment 19. The method of any one of embodiments 1 to 18, wherein the brominating agent is selected from HBr, Br2, and combinations thereof.

[0027] Embodiment 20 The method of any one of embodiments 1 to 19, wherein the brominating agent is HBr.

[0028] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the strong acid is selected from sulfuric acid, hydrogen bromide, an acid stronger than hydrogen bromide, and combinations thereof.

[0029] Embodiment 22 The method of any one of embodiments 1 to 21, wherein the strong acid is sulfuric acid.

[0030] Embodiment 23. The method of any one of embodiments 1 to 22, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and combinations thereof.

[0031] Embodiment 24 The method of any one of embodiments 1 to 23, wherein the base is sodium hydroxide.

[0032] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the method step of adding a base to the mixture comprises adding the base to the mixture dropwise.

[0033] Embodiment 26 The method of any one of embodiments 1 to 25, wherein at least one method step further comprises agitating the mixture.

[0034] Embodiment 27. The method of any one of embodiments 1 to 26, wherein at least one method step further comprises cooling the mixture to a temperature in the range of about 0° C. to about 5° C.

[0035] Embodiment 28. The method of any one of embodiments 1 to 27, wherein at least one method step further comprises heating the mixture to a temperature in the range of about 8° C. to about 12° C.

[0036] In one embodiment, ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate is prepared according to the method depicted in Scheme 1. [ka]

[0037] In one embodiment, compounds of formula II are prepared according to the method depicted in Scheme 2. The R groups, X, Y, n, and m are as defined elsewhere in this disclosure. [ka]

[0038] This embodiment includes forming a mixture including a compound of formula I, a solvent, and optionally a bromide, introducing a brominating agent to the mixture, introducing a strong acid to the mixture, and optionally adding a base to the mixture.

[0039] In some embodiments, the solvent is selected from dibromomethane, dichloromethane, acetic acid, ethyl acetate, acetonitrile, dichloroethane, dibromoethane, and combinations thereof.

[0040] Generally, any suitable amount of acetic acid can be used in the solvent. In many embodiments, the amount of acetic acid is relatively low to reduce acetic acid usage and waste. Too little acetic acid will not aid in the reaction, while a relatively large amount of acetic acid will cause more waste. In some embodiments, the solvent comprises an amount of acetic acid ranging from about 0.1 equivalents to about 10 equivalents. In some embodiments, the solvent comprises an amount of acetic acid ranging from about 0.5 equivalents to about 6 equivalents. In some embodiments, the solvent comprises an amount of acetic acid ranging from about 0.7 equivalents to about 3 equivalents. In some embodiments, the solvent comprises an amount of acetic acid ranging from about 0.9 equivalents to about 1.5 equivalents. In some embodiments, the solvent comprises an amount of acetic acid of about 1.0 equivalents.

[0041] In some embodiments, the bromide is selected from phosphorus oxybromide, phosphorus pentabromide, phosphorus tribromide, dibromo trialkyl phosphine, and dibromo diphenyl phosphine, and combinations thereof. In some embodiments, the bromide reduces the water content.

[0042] In some embodiments, the brominating agent is selected from HBr, Br2, and combinations thereof. In some embodiments, the brominating agent is HBr.

[0043] Generally, any suitable amount of brominating agent may be used. In many embodiments, the brominating agent is particularly useful for reducing waste.

[0044] In some embodiments, the brominating agent is present in an amount ranging from about 0.1 equivalents to about 10 equivalents. In some embodiments, the brominating agent is present in an amount ranging from about 0.5 equivalents to about 6 equivalents. In some embodiments, the brominating agent is present in an amount ranging from about 0.7 equivalents to about 3 equivalents. In some embodiments, the brominating agent is present in an amount ranging from about 0.9 equivalents to about 1.5 equivalents. In some embodiments, the brominating agent is present in an amount of about 1.3 equivalents.

[0045] Generally, the strong acid is any suitable strong acid known in the art that has an acidity stronger than hydrogen bromide. In some embodiments, the strong acid is selected from sulfuric acid, hydrogen bromide, acids stronger than hydrogen bromide, and combinations thereof. In some embodiments, the strong acid is sulfuric acid.

[0046] In some embodiments, the base is the wash solution. In some embodiments, the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and combinations thereof. In some embodiments, the base is sodium hydroxide.

[0047] In some embodiments, the method step of adding a base to the mixture comprises adding the base to the mixture dropwise.

[0048] In some embodiments, at least one method step further comprises agitating the mixture.

[0049] Generally, cooling the reaction mixture during the addition of the brominating agent and the strong acid benefits the reaction. At higher temperatures, reduced yields and high impurities are observed. In some embodiments, at least one process step further comprises cooling the mixture to a temperature of less than about 5° C.

[0050] Generally, cooling the reaction mixture during the optional wash steps in which a base is added to the mixture helps reduce side reactions. In some embodiments, at least one process step further comprises cooling the mixture to a temperature of less than about 10° C.

[0051] In some embodiments, at least one method step further comprises cooling the mixture to a temperature in the range of about 0°C to about 5°C.

[0052] In some embodiments, at least one method step further comprises heating the mixture to a temperature in the range of about 8°C to about 12°C. EXAMPLES

[0053] Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent using the preceding description. Thus, the following examples are merely illustrative and should not be construed as limiting the present disclosure in any manner. The starting materials in the following examples may not necessarily have been prepared by the specific preparative experiments whose procedures are described in other examples. It is also understood that any numerical range cited herein includes 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 are expressly recited herein. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​therebetween, including the lowest and highest values ​​recited, are to be considered as expressly recited herein.

[0054] Example 1. Bromination quantified by equivalents. 1.0 equivalent of ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate in dichloromethane is cooled to about 0-5°C in a reactor, and about 1.0 equivalent of acetic acid and about 0.02 equivalent of PBr3 are fed to the reactor. Then, 1.3 equivalent of hydrogen bromide gas is introduced into the reactor at about 0-5°C. Then, 0.95 equivalent of sulfuric acid is fed to the reactor. The reaction mixture in the reactor is heated and maintained at about 8-12°C for 4 hours. After the reaction is completed, the reaction mass is washed by dropwise addition of 3.6 equivalents of 10 wt% NaOH aqueous solution to the reaction mixture with stirring at less than 10°C, followed by removal of the aqueous phase by phase separation at 20-25°C. Finally, a second wash is performed by charging the organic phase with 0.4 equivalents of 2 wt% NaOH solution at 0-10° C. to give a pH above 12. The phases are separated to give ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate solution in about 91.6% yield.

[0055] Example 2. Small scale bromination. 400 g of ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate in dichloromethane is cooled to about 0-5° C. in a reactor, and 14.6 g of acetic acid and 1.3 g of PBr3 are fed to the reactor. Then, 25.2 g of hydrogen bromide is introduced into the reactor at about 0-5° C. Then, 22.6 g of sulfuric acid is fed to the reactor. The reaction mixture in the reactor is heated and maintained at about 8-12° C. for 4 hours. After the reaction is completed, the reaction mass is washed twice by using 10% and 2% NaOH aqueous solutions. The typical yield of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate is about 90.15%.

[0056] Example 3. Large scale bromination. 200 kg of ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate in dichloromethane is cooled to about 0-5°C in a reactor, and 7.1 kg of acetic acid and 0.64 kg of PBr3 are fed to the reactor. Then, 12.6 kg of hydrogen bromide is introduced into the reactor at about 0-5°C. Then, 11.3 kg of sulfuric acid is fed to the reactor. The reaction mixture in the reactor is heated and maintained at about 8-12°C for 4 hours. After the reaction is completed, the reaction mass is washed twice by using 10% and 2% NaOH aqueous solutions. The typical yield of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate is about 91.6%.

[0057] Compared to conventional processes, the process according to the present disclosure exhibits comparable yields with much less waste, much less brominating agent, and much less solvent.

[0058] This written description uses examples to explain 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 words of the claims, or if they include equivalent structural elements that differ only insignificantly from the literal words of the claims.

[0059] 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 limitations expressly stated. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited only to those elements and may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0060] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. When in a claim, such would close the claim to the inclusion of materials other than those recited, with the exception of impurities normally associated with it. When the phrase "consisting of" appears in a clause in the body of a claim rather than immediately following the preamble, it limits only the elements recited in that clause; other elements are not excluded from the claim as a whole.

[0061] The transitional phrase "consisting essentially of" is used to define compositions or methods that include additional materials, steps, features, ingredients, or elements in addition to those literally disclosed, provided that those additional materials, steps, features, ingredients, or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of" occupies a middle ground between "comprising" and "consisting of."

[0062] It should be readily understood that where an invention or part thereof is defined by open-ended terms such as "comprising," the description should also be construed as describing such invention using the terms "consisting essentially of" or "consisting of" (unless otherwise specified).

[0063] Further, unless expressly stated to the contrary, "or" refers to an inclusive or, not an 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 both A and B are true (or exist).

[0064] 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 the element or component. Thus, "a" or "an" should be read to include one or at least one, and singular forms of elements or components also include plurals unless the number is clearly intended to be singular.

[0065] As used herein, the term "about" means plus or minus 10% of the value.

[0066] The term "alkyl" used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched-chain alkyl such as methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers.

[0067] The term "alkenyl" can include straight-chain or branched alkenes, such as 1 propenyl, 2 propenyl, and the different butenyl, pentenyl, and hexenyl isomers. "Alkenyl" also includes polyenes, such as 1,2 propadienyl and 2,4 hexadienyl.

[0068] The term "alkynyl" includes straight-chain or branched alkynes, such as 1 propynyl, 2 propynyl, and the different butynyl, pentynyl, and hexynyl isomers. "Alkynyl" can also include moieties composed of multiple triple bonds, such as 2,5 hexadiynyl.

[0069] The term "alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the different butoxy, pentoxy, and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2, and CH3CH2OCH2CH2.

[0070] The term "alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, and hexylthio isomers.

[0071] The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Cycloalkylalkyl" refers to an alkyl group substituted with a cycloalky group, including, for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl, and cyclohexylmethyl.

[0072] The term "cycloalkylamino" means that the amino nitrogen atom is bound to a cycloalkyl radical and a hydrogen atom, and includes groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, and cyclohexylamino. "(Alkyl)cycloalkylamino" means a cycloalkylamino group in which a hydrogen atom has been replaced by an alkyl radical; example groups include (alkyl)cyclopropylamino, (alkyl)cyclobutylamino, (alkyl)cyclopentylamino, and (alkyl)cyclohexylamino.

[0073] The term "aryl" refers to an aromatic ring or ring system or a heteroaromatic ring or ring system, each of which is optionally substituted. The term "aromatic ring system" refers to fully unsaturated carbocyclic and heterocyclic rings, in which at least one ring of the polycyclic ring system is aromatic. Aromatic refers to each of the ring atoms essentially lying in the same plane, having p orbitals perpendicular to the plane of the ring, and having (4n+2) pi electrons associated with the ring according to Huckel's rule, where n is 0 or a positive integer. The term "aromatic carbocyclic ring system" includes fully aromatic carbocyclic rings and carbocyclic rings in which at least one ring of the polycyclic ring system is aromatic (e.g., phenyl and naphthyl). The term "heteroaromatic ring or ring system" includes all aromatic heterocycles as well as heterocycles that may contain 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, provided that at least one ring of a polycyclic ring system is aromatic and at least one ring atom is not carbon, and each heteroaromatic ring contains no more than four nitrogens, no more than two oxygens, and no more than two sulfurs (where aromatic indicates that Huckel's rule is satisfied). The heterocyclic ring system may be attached via any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. More specifically, the term "aryl" refers to the moiety [ka] In the formula, R 2 and n is defined above, and the "3" indicates the 3-position of the substituent on the moiety.

[0074] The term "halogen", either alone or in a compound word such as "haloalkyl", includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in a compound word such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" include F3C, ClCH2, CF3CH2, and CF3CCl2. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy", and the like are defined similarly to the term "haloalkyl". Examples of "haloalkenyl" include (Cl)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC≡CCHCl, CF3C≡C, CCl3C≡C, and FCH2C≡CCH2. Examples of "haloalkoxy" include CF3O, CCl3CH2O, HCF2CH2CH2O, and CF3CH2O.

[0075] The terms "alkylaminocarbonyl" and "dialkylaminocarbonyl" include, for example, CH3NHC(=O), CH3CH2NHC(=O), and (CH3)2NC(=O).

[0076] The total number of carbon atoms in the substituent is "C i ~C j " prefix. For example, C1-C3 alkylsulfonyl denotes methylsulfonyl to propylsulfonyl. In the above enumeration, when the compound of formula (I) contains a heteroaromatic ring, all substituents are attached to the ring via any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.

[0077] The group is a substituent that may be hydrogen, e.g., R 4 It will be recognized that when this substituent is considered to be hydrogen, this is equivalent to said group being unsubstituted.

[0078] Certain compounds of the present invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Those skilled in the art will recognize that a stereoisomer may be more active and / or exhibit beneficial effects when enriched with respect to other stereoisomers or separated from other stereoisomers. Furthermore, those skilled in the art know how to separate, enrich, and / or selectively prepare said stereoisomers.

Claims

1. A process for preparing a compound of formula (II) 【Chemistry 1】 (In the formula, R ５ is a halogen; Each R ６ are independently １ ~C ４ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C ３ ~C ６ Cycloalkyl, C １ ~C ４ Haloalkyl, C ２ ~C ４ Haloalkenyl, C ２ ~C ４ Haloalkynyl, C ３ ~C ６ Halocycloalkyl, halogen, CN, NO ２ , C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkoxy, C １ ~C ４ Alkylthio, C １ ~C ４ Alkylsulfinyl, C １ ~C ４ Alkylsulfonyl, C １ ~C ４ Alkylamino, C ２ ~C ８ Dialkylamino, C ３ ~C ６ Cycloalkylamino, C ３ ~C ６ (Alkyl)cycloalkylamino, C ２ ~C ４ Alkylcarbonyl, C ２ ~C ６ Alkoxycarbonyl, C ２ ~C ６ Alkylaminocarbonyl, C ３ ~C ８ Dialkylaminocarbonyl, or C ３ ~C ６ trialkylsilyl; R ７ is H or C １ ~C ４ is alkyl; Y is N or CR ８ and R ８ is H or R ６ and m is 0, 1, 2, or 3, with the proviso that when X is CH, m is at least 1. I) forming a mixture comprising: A) Compound of formula (I) 【Chemistry 2】 (In the formula, R １ is a sulfonate; Each R ２ are independently １ ~C ４ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C ３ ~C ６ Cycloalkyl, C １ ~C ４ Haloalkyl, C ２ ~C ４ Haloalkenyl, C ２ ~C ４ Haloalkynyl, C ３ ~C ６ Halocycloalkyl, halogen, CN, NO ２ , C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkoxy, C １ ~C ４ Alkylthio, C １ ~C ４ Alkylsulfinyl, C １ ~C ４ Alkylsulfonyl, C １ ~C ４ Alkylamino, C ２ ~C ８ Dialkylamino, C ３ ~C ６ Cycloalkylamino, C ３ ~C ６ (Alkyl)cycloalkylamino, C ２ ~C ４ Alkylcarbonyl, C ２ ~C ６ Alkoxycarbonyl, C ２ ~C ６ Alkylaminocarbonyl, C ３ ~C ８ Dialkylaminocarbonyl, or C ３ ~C ６ trialkylsilyl; R ３ is H or C １ ~C ４ is alkyl; X is N or CR ４ and R ４ is H or R ２ and n is 0, 1, 2, or 3, with the proviso that when X is CH, n is at least 1; B) a solvent; and C) optionally bromide; II) introducing a brominating agent into said mixture; III) introducing a strong acid into the mixture; and IV) Optionally adding a base to the mixture. The method includes:

2. 2. The method of claim 1 , wherein m is 1, 2, or 3.

3. R ５ The method according to claim 1 or 2, wherein is Cl or Br.

4. R ６ The method of any one of claims 1 to 3, wherein is independently Cl or Br.

5. One R ６ The method of any one of claims 1 to 4, wherein:

6. R ７ C １ ~C ４ The method according to any one of claims 1 to 5, wherein the alkyl group is an alkyl group.

7. The method of any one of claims 1 to 6, wherein Y is N.

8. The method of any one of claims 1 to 7, wherein the compound of formula (II) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate having the following structure: 【Chemistry 3】

9. The method of any one of claims 1 to 8, wherein n is 1, 2, or 3.

10. R １ The method according to any one of claims 1 to 9, wherein is selected from methanesulfonate, benzenesulfonate, and p-toluenesulfonate.

11. R ２ The method of any one of claims 1 to 10, wherein is independently Cl or Br.

12. One R ２ The method of any one of claims 1 to 11, wherein:

13. R ３ C １ ~C ４ The method of any one of claims 1 to 12, wherein the alkyl group is an alkyl group.

14. The method of any one of claims 1 to 13, wherein X is N.

15. The method of any one of claims 1 to 14, wherein the compound of formula (I) is ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate, having the following structure: 【Chemistry 4】

16. 16. The method of any one of claims 1 to 15, wherein the solvent is selected from dibromomethane, dichloromethane, acetic acid, ethyl acetate, acetonitrile, dichloroethane, dibromoethane, and combinations thereof.

17. 17. The process of any one of claims 1 to 16, wherein the solvent comprises acetic acid in an amount ranging from about 0.1 equivalents to about 10 equivalents, preferably from about 0.5 equivalents to about 6 equivalents.

18. 18. The method of any one of claims 1 to 17, wherein the bromide is selected from phosphorus oxybromide, phosphorus pentabromide, phosphorus tribromide, dibromotrialkylphosphines and dibromodiphenylphosphines, and combinations thereof.

19. The brominating agent is HBr, Br ２ The method of any one of claims 1 to 18, wherein the compound is selected from the group consisting of:

20. The process according to any one of claims 1 to 19, wherein the brominating agent is HBr.

21. 21. The method of any one of claims 1 to 20, wherein the strong acid is selected from sulfuric acid, hydrogen bromide, an acid stronger than hydrogen bromide, and combinations thereof.

22. The method according to any one of claims 1 to 21, wherein the strong acid is sulfuric acid.

23. 23. The method of any one of claims 1 to 22, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and combinations thereof.

24. The process according to any one of claims 1 to 23, wherein the base is sodium hydroxide.

25. 25. The method of any one of claims 1 to 24, wherein the method step of adding a base to the mixture comprises adding a base to the mixture dropwise.

26. The method of any one of claims 1 to 25, wherein at least one method step further comprises agitating the mixture.

27. 27. The method of any one of claims 1 to 26, wherein at least one method step further comprises cooling the mixture to a temperature in the range of from about 0°C to about 5°C.

28. 28. The method of any one of claims 1 to 27, wherein at least one method step further comprises heating the mixture to a temperature in the range of about 8°C to about 12°C.

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