Preparation of substituted pyrazoles and their use as anthranilamide precursors.

Abstract

Disclosed are methods for preparing the pyrazole derivative 3-bromo-5-methyl-1-H-pyrazole-N-2-chloropyridine (compound of formula I) by reacting a compound of formula II with a halogen-substituted pyridine, optionally in the presence of a base and an organic solvent, or by decarboxylating a pyrazole carboxylic acid of formula XI in the presence of an acid. Also provided are methods for preparing synthetic precursors of formulas II, IV, V, VI, and XI, as well as a method for preparing a compound of formula VII, comprising reacting a compound of formula I with an oxidant, optionally in the presence of a catalyst. Compounds of formula I are also disclosed as synthetic precursors useful for preparing anthranilamides of formula VIII. [Formula 1] JPEG2022529475000052.jpg85163

Description

[Technical Field]

[0001] Relationship with related applications This application claims the benefit of Chinese Patent Application No. 201910317694.4, filed on April 19, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to the preparation of substituted pyrazole derivatives and their further conversion into pesticidal active anthranilic acid amide compounds, in particular chlorantraniliprole. [Background technology]

[0003] Background of the Invention Pyrazoles are nitrogen-containing five-membered heterocyclic compounds that constitute a widely useful class of compounds in organic synthesis. They are one of the most studied groups of compounds within the nitrogen-containing heterocycle class due to their occurrence in different structures with diverse applications, particularly in agriculture. In fact, numerous synthetic methods leading to pyrazole precursors of active pesticides have been reported over the years.

[0004] Particularly interesting active pesticides are the anthranilamide insecticides, particularly chlorantraniliprole, previously disclosed, for example, in International Patent Applications WO 02 / 04999, WO 02 / 04999, WO 02 / 04999, and WO 02 / 04999. Several pyrazole precursors leading to the preparation of said anthranilamides, and methods for their preparation, are disclosed, for example, in International Patent Applications WO 02 / 04999, ...

[0005] Additionally, International Patent Applications JP 2003-129999 and JP 2003-129999 both disclose a general method for alkylating substituted methylpyrazoles and further oxidizing the methyl group with potassium permanganate to produce pyrazole carboxylic acids as precursors for preparing anthranilamides. However, these types of transformations refer only to alkyl and / or haloalkyl substituents on the pyrazole ring and do not provide industrial-scale methods for preparing the starting methylpyrazoles. Therefore, there remains a need for efficient industrial-scale methods for producing the starting methylpyrazoles and further converting these halogen-substituted methylpyrazoles to pyrazole carboxylic acid precursors of chlorantraniliprole via alkylation and subsequent efficient oxidation of the methyl group. There is a need for more cost-effective, large-scale industrial methods for preparing pyrazole carboxylic acid precursors of chlorantraniliprole in general. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2001 / 070671 Pamphlet [Patent Document 2] International Publication No. 2003 / 015519 Pamphlet [Patent Document 3] International Publication No. 2003 / 015518 Pamphlet [Patent Document 4] International Publication No. 2006 / 062978 Pamphlet [Patent Document 5] International Publication No. 2003 / 016283 Pamphlet [Patent Document 6] International Publication No. 2004 / 011447 Pamphlet [Patent Document 7] International Publication No. 2003 / 015519 Pamphlet [Patent Document 8] International Publication No. 1998 / 040358 Pamphlet [Patent Document 9] European Patent No. 0333131 [Patent Document 10] European Patent No. 0151866 [Patent Document 11] U.S. Patent No. 3,254,093 [Patent Document 12] International Publication No. 2003 / 016300 Brochure Summary of the Invention

[0007] The present invention relates to the preparation of the pyrazole derivative 3-bromo-5-methyl-1-H-pyrazole-N-2-chloropyridine (compound of formula I) by reacting a compound of formula II with a halogen-substituted pyridine, optionally in the presence of a base and an organic solvent. [ka]

[0008] Further according to the present invention, a compound of formula IV [ka] with a base to obtain a compound of formula V, and further decarboxylating the compound of formula V in the presence of an acid, or reacting a compound of formula IV with an acid to obtain a compound of formula II.

[0009] Additionally, the present invention relates to a process for preparing a compound of formula IV, comprising contacting a compound of formula VI with a brominating agent, optionally in the presence of a base and an organic solvent. [ka]

[0010] Additionally, the present invention relates to a process for preparing a compound of formula I, which comprises decarboxylating a compound of formula XI in the presence of an acid. [ka]

[0011] The present invention further includes a method for preparing a compound of formula XI, comprising: a) contacting a compound of formula XII with a brominating agent, optionally in the presence of a base and an organic solvent, to obtain a compound of formula XIII; and b) contacting the compound of formula XIII with an acid. [ka]

[0012] Additionally, the present invention relates to a compound of formula IV [ka] In the formula, R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy. phenyl, optionally substituted phenyl or optionally substituted benzyl by contacting a compound of formula V with a base [ka] and b) converting the compound of formula V into a compound of formula III [ka]

[0013] where L is a leaving group with pyridine in the presence of a base and an organic solvent, optionally in the presence of a catalyst. The present invention is directed to a method for preparing a compound of formula XI, comprising:

[0014] Additionally, the present invention relates to a process for preparing compounds of formula I from compounds of formula XI prepared as described above.

[0015] The present invention further provides a compound of formula I [ka] The present invention provides a compound of the formula:

[0016] Additionally, the present invention provides a compound of formula VII, which comprises reacting a compound of formula I with an oxidant, optionally in the presence of a catalyst. [ka] The present invention provides a method for preparing the compound of formula (I).

[0017] The present invention also uses compounds of formula I to produce compounds of formula VIII

[0018] [ka] This invention includes a method for preparing the compound of formula (I).

[0019] The present invention also provides a method for preparing a compound of formula I by reacting the compound of formula I with an oxidant, optionally in the presence of a catalyst, to obtain a compound of formula VII; and then converting the compound of formula VII into an ortho-aminoaromatic carboxylic acid IX. [ka] to give the corresponding benzoxazinone X [ka] and then reacting the resulting benzoxazinone X with methylamine to give formula VIII obtaining a compound of formula VIII [ka] This invention includes a method for preparing the compound of formula (I).

[0020] The present invention further provides a method for the preparation of a compound of formula I by reacting the compound of formula I with an oxidant, optionally in the presence of a catalyst, to obtain a compound of formula VII, and then converting the compound of formula VII to an anthranilic acid amide XIV. [ka] to obtain a compound of formula VIII [ka] The present invention provides a method for preparing the compound of formula (I).

[0021] An additional aspect of the present invention relates to a method for preparing a compound of formula VIII using a compound of formula I prepared as shown above.

[0022] An additional aspect of the present invention relates to a method for preparing a compound of formula VIII using a compound of formula VII prepared as shown above.

[0023] A further aspect of the present invention relates to a method for preparing a compound of formula VIII using a compound of formula II prepared as shown above.

[0024] A further aspect of the present invention relates to a method for preparing a compound of formula VIII using a compound of formula XI prepared as shown above. DETAILED DESCRIPTION OF THE INVENTION

[0025] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," and derivatives thereof are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, or method comprising a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent in such composition, mixture, process, or method.

[0026] The transitional phrase "consisting of" excludes any unspecified element, step, or material. If a claim, it closes the claim against the inclusion of substances other than those recited, except for impurities ordinarily associated therewith. The appearance of the phrase "consisting of" in a clause in the body of a claim limits the claim to only the elements recited in that clause, rather than following immediately in the preamble, and does not exclude other elements from the claim as a whole.

[0027] The transitional phrase "consisting essentially of" is used to define compositions or methods that include, in addition to those literally disclosed, additional materials, steps, functions, ingredients, or elements, provided that these additional materials, steps, functions, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of" occupies a position between "comprising" and "consisting of."

[0028] It should be readily understood that where an applicant defines the invention or any portion thereof with open-ended terms such as "comprising," the description (unless otherwise indicated) should also be construed to describe such inventions using the terms "consisting essentially of" or "consisting of."

[0029] Furthermore, unless clearly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or." For example, condition A or B is satisfied by 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 (exists), and A and B are true (or exist).

[0030] 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" and "an" should be read as one or at least one, and the singular form of an element or component also includes the plural unless the number clearly indicates singularity.

[0031] Certain compounds of the present invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, and geometric isomers. One skilled in the art will recognize that one stereoisomer may be more active and / or exhibit advantageous effects when enriched with respect to or separated from other stereoisomer(s). Furthermore, one skilled in the art will know how to separate, enrich, and / or selectively prepare such stereoisomers. Thus, compounds of the present invention can exist as a mixture of stereoisomers, individual stereoisomers, or optically active forms.

[0032] The term "halogen," whether alone or in a combined term such as "haloalkyl," includes fluorine, chlorine, bromine, or iodine. Furthermore, when a combined term such as "haloalkyl" is used, the alkyl can 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 term "haloalkoxy" includes CF3O, CCl3CHO, HCF2CH2CH2O, and CF3CHO.

[0033] According to an embodiment, a compound of formula I is prepared by reacting a compound of II with a pyridine of formula III in the presence of a base and an organic solvent, optionally in the presence of a catalyst, as shown in Scheme I, where L is a leaving group: [ka]

[0034] Scheme 1 L can be any leaving group compatible with the prevailing reaction conditions, for example, L can be a halogen or an optionally halogenated sulfonyl group.

[0035] According to an embodiment, suitable bases used in the reaction are selected from the group consisting of alkali and alkaline earth hydroxides, hydrides, alkoxides and salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid and citric acid. More preferably, suitable bases are alkali metal carbonates and / or alkali metal hydroxides.

[0036] The suitable base used in the process steps was generally used in an amount of 0.01 to 100.0 moles, more preferably 0.1 to 10.0 moles, particularly 1.0 to 5.0 moles, and especially 1.2 to 2.0 moles, based in each case on 1 mole of the compound of formula II.

[0037] According to another embodiment, the organic solvent can be selected from the group consisting of polar or non-polar organic solvents, such as C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas, and mixtures thereof. Suitable polar solvents can be, for example, but not limited to, alcohols (preferably C1-C4 alcohols), acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylethanolamine, or mixtures thereof. In an embodiment, the suitable solvent comprises N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, n-butanol, ethanol, or mixtures thereof. In a preferred embodiment, the suitable polar organic solvent comprises N,N-dimethylacetamide, dimethyl sulfoxide, or mixtures thereof. Suitable non-polar organic solvents can be, for example, but not limited to, C1-C6 alkanes, C1-C6 halogenated alkanes, aromatic solvents such as benzene, xylene, nitrobenzene, and / or ethers such as 1,4-dioxane, or mixtures thereof.

[0038] Suitable catalysts are selected from the group consisting of alkali fluorides such as CsF, KF, NaF, quaternary ammonium salts such as tetraethylammonium hydrogen sulfate and triethylbenzylammonium chloride, phosphonium salts such as tetraphenylphosphonium bromide, PEGs, crown ethers, and mixtures thereof.

[0039] A suitable molar ratio of catalyst to pyrazole compound of formula II is 0.001 to 100 mol / mol, especially 0.01 to 10.0 mol / mol.

[0040] The reactants can in principle be contacted with each other in any desired order, e.g. The compound of formula II and the pyridine of formula III, each optionally dissolved or dispersed in a solvent, are added first, and then the base, optionally dissolved or dispersed, is added, or conversely, the base, optionally dissolved or dispersed in a solvent, is added first. Compound II can then be mixed in. Alternatively, the two reactants can be added to the reaction vessel simultaneously.

[0041] According to an embodiment, a compound of formula II is prepared as shown in Scheme 2. The process includes contacting a compound of formula IV (wherein R is C-C alkyl, C-C alkoxy, C-C cycloalkyl, optionally substituted phenyl, or optionally substituted benzyl) with a base to obtain a compound of formula V, and further providing a compound of formula II by decarboxylation of the compound of formula V in the presence of an acid, or alternatively by contacting the compound of formula IV with an acid. [ka]

[0042] Scheme 2 Preparation of Compounds of Formula II According to an embodiment, the compound of formula IV is heated with a base, preferably to a temperature of 90° C. to 120° C., more preferably to a temperature of 100° C. The resulting compound of formula V is isolated after cooling the reaction mixture to a temperature of 5 to 10° C. and further quenching with an acid. Suitable bases are selected from the group consisting of alkali and alkaline earth hydroxides, hydrides, alkoxides and salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid and citric acid, preferably selected from alkali metal hydroxides or alkoxides such as sodium hydroxide, potassium hydroxide, potassium t-butoxide, etc.

[0043] According to an embodiment, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, and mixtures thereof.

[0044] According to another embodiment, the resulting compound of formula V is converted to a compound of formula II by heating the compound of formula V preferably at a temperature of 90° C. to 120° C., more preferably at a temperature of 100-105° C., with 30-60% by volume of an acid such as hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0045] According to another embodiment, said conversion of a compound of formula IV to a compound of formula II can be carried out as a one-step process without isolating the compound of formula V.

[0046] According to another embodiment, the compound of formula II is obtained by a one-pot process which comprises heating the compound of formula IV, preferably at a temperature of 90°C to 120°C, more preferably at a temperature of 100-110°C, with 30-60% by volume of an acid such as hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0047] According to an embodiment, compounds of formula IV are prepared by bromination of a compound of formula VI, where R is as defined above, comprising contacting a compound of formula VI with a brominating agent, optionally in the presence of a base and an organic solvent, as shown in Scheme 3.

[0048] According to an embodiment, suitable bases are selected from the group consisting of alkali and alkaline earth hydroxides, hydrides, alkoxides and salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid and citric acid.

[0049] According to another embodiment, the suitable organic solvent is selected from the group consisting of C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas, and mixtures thereof.

[0050] Any brominating agent capable of generating electrophilic bromide ions (Br+) in the bromination process can be used. Non-limiting examples of such brominating agents include bromine (Br2), N-bromosuccinimide (NBS), dibromodimethylhydantoin, N-bromophthalimide, N-bromosaccharin, monosodium bromoisocyanurate hydrate, dibromoisocyanuric acid (=DBI), bromodimethylsulfonium bromide, 5,5-dibromoMeldrum's acid CAS RN: 66131-14-4, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate, and BrCl, and mixtures thereof. According to an embodiment, the suitable brominating agent is selected from bromine (Br2), N-bromosuccinimide (NBS), and / or N-bromophthalimide.

[0051] According to an embodiment, a process is used in which the brominating agent is selected from a range of values ​​between 0.01 and 10.0 molar equivalents relative to the starting compound of formula VI.

[0052] According to an embodiment, the process is used in the presence of a base.

[0053] An embodiment of this type is a process wherein the amount of base used is an amount selected from the range of values ​​between 0.01 and 10.0 molar equivalents relative to the starting compound of formula VI. [ka]

[0054] Scheme 3 Preparation of Compounds of Formula IV In embodiments, the bromination process can be carried out in the presence of an organic solvent. Suitable organic solvents include acetonitrile, propionitrile, and halogenated saturated aliphatic hydrocarbons such as lower alkyl halides, e.g., dichloromethane, carbon tetrachloride, chloroform, bromochloromethane, 1,1,2-trichloroethane, 1,2-dibromoethane, dibromomethane, , ethylene dichloride, etc. Liquid saturated hydrocarbon diluents are also suitable and are represented by materials such as cyclohexane, methylcyclohexane, 1,3-dimethylcyclohexane, 1,4-dimethylcyclohexane, isopropylcyclohexane, etc. In another embodiment, the process is carried out in the presence of a base and an organic solvent.

[0055] In the practice of the present invention, the reaction temperature is maintained in the range of 0 to 50° C., and preferably in the range of 15 to 30° C., for substantially the entire reaction period, i.e., until all of the brominating agent and compound of Formula VI have been mixed together. Temperature control is preferably maintained by adding the brominating agent to the compound of Formula VI in portions, since the bromination reaction is exothermic.

[0056] Compounds of formula VI can be prepared by known methods, for example as generally disclosed in Journal of Heterocyclic Chemistry, Volume 46, Issue 5, Pages 801-827. In particular, Scheme 4 depicts the preparation of compounds of formula VIa via the reaction of dimethylformamide dimethylacetal with ethyl acetoacetate by formylation via the active methylene group, followed by further reaction with hydrazine hydrate. [ka]

[0057] Scheme 4 Preparation of compounds of formula VIa In accordance with the present invention, compounds of formula VII are prepared by reacting compounds of formula I with an oxidant, optionally in the presence of a catalyst, as shown in Scheme 5. [ka]

[0058] Scheme 5 Preparation of Compounds of Formula VII The compound of formula VII, including various methods for its preparation, was previously disclosed in WO 2003 / 015519 and WO 2003 / 015518.

[0059] According to an embodiment, the aforementioned oxidation reaction comprises a solvent selected from water, inert alcohols, carboxylic acids and their esters, chlorinated hydrocarbons, sulfoxides, sulfones, amides, ethers, ketones, pyridines, and mixtures thereof, wherein the solvent selected requires partial or complete dissolution of the starting compound of formula I.

[0060] According to an embodiment, the oxidant is selected from the group consisting of permanganates such as potassium permanganate, sodium permanganate, organic and inorganic peroxides such as benzoyl peroxide, tert-butyl peroxide, sodium peroxide, hydrogen peroxide, oxygen (diluted or undiluted O2, O3) or mixtures thereof.

[0061] According to another embodiment, the oxidation reaction is carried out in the presence of a catalyst, suitable catalysts being selected from the group consisting of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, tetraethylammonium hydrogen sulfate, quaternary ammonium salts such as triethylbenzylammonium chloride, phosphonium salts such as tetraphenylphosphonium bromide, PEGs, crown ethers, sodium nitrite, tert-butyl nitrite, cobalt(II) acetate, manganese(II) acetate, and mixtures thereof.

[0062] According to another embodiment, the oxidation reaction is carried out in the presence of N-hydroxysuccinimide, N-hydroxyphthalimide, and a catalyst selected from the group consisting of sodium nitrite, tert-butyl nitrite, cobalt(II) acetate, manganese(II) acetate, and mixtures thereof.

[0063] According to another embodiment, the oxidation reaction can be carried out in the presence of a solvent selected from the group consisting of a C1-C6 alcohol such as tert-butyl alcohol, an organic nitrile such as acetonitrile, a carboxylic acid such as acetic acid, or a halogenated derivative thereof.

[0064] A suitable molar ratio of catalyst to pyrazole compound of formula I is from 0.001 to 100 mol / mol, especially from 0.01 to 10.0 mol / mol.

[0065] The oxidation reaction proceeds particularly smoothly when the molar ratio of the oxidant to the pyrazole compound of formula I is 0.1 to 100 mol / mol, particularly 1.0 to 10.0 mol / mol.

[0066] Finally, the reaction mixture containing the oxidation product is processed, which may include filtration, purification, acidification (pH<4), extraction, concentration, and recrystallization. Optimization of these steps leads to purities greater than 90%.

[0067] In accordance with the present invention, the compound of formula I is preferably contacted with the oxidant at elevated temperatures, i.e., temperatures above room temperature (20° C.). A preferred temperature interval is 50 to 120° C., most preferred is 70 to 120° C. While not limiting the scope of protection, elevated temperatures are likely to facilitate dissolution of the compound of formula I for more effective oxidation.

[0068] According to another aspect of the invention, a compound of formula I may be prepared by reacting a compound of formula XI as shown in Scheme It is prepared by decarboxylation of [ka]

[0069] Scheme 6 Preparation of compounds of formula I from compounds of formula XI Suitable acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0070] In the practice of the present invention, the decarboxylation temperature is in the range of 10 to 30°C, and preferably 100 The temperature is maintained in the range of 100 to 120°C.

[0071] A catalytic amount of acid is generally sufficient for the reaction, and the acid is generally used in an amount of 0.1 to 1000 moles, and particularly 1.0 to 10.0 moles, per mole of compound of formula XI.

[0072] Typically, the decarboxylation reaction is carried out in the presence of an organic solvent or a mixture of solvents. Suitable organic solvents are protic polar solvents, such as aliphatic alcohols, preferably having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol; carboxylic acids, such as acetic acid; aromatic polar solvents, such as aromatic hydrocarbons, such as benzene, toluene, xylene, cumene, chlorobenzene, nitrobenzene or tert-butylbenzene; aprotic solvents, such as cyclic or acyclic ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, tetrahydrofuran (THF) or dioxane; cyclic or acyclic amides, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetramethylurea; or aliphatic nitriles, such as acetonitrile or propionitrile, and mixtures thereof.

[0073] According to another aspect of the present invention, a compound of formula XI can be prepared as shown in Scheme 7 by: a) contacting a compound of formula XII with a brominating agent, optionally in the presence of a base and an organic solvent, to obtain a compound of formula XIII; and b) contacting a compound of formula XIII with an acid. [ka]

[0074] Scheme 7 Preparation of Compounds of Formula XI According to an embodiment, suitable brominating agents are selected from the group consisting of bromine (Br), N-bromosuccinimide (NBS), dibromodimethylhydantoin, N-bromophthalimide, N-bromosaccharin, bromoisocyanuric acid monosodium hydrate, dibromoisocyanuric acid (=DBI), bromodimethylsulfonium bromide, 5,5-dibromoMeldrum's acid CAS RN: 66131-14-4, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate, and BrCl, and mixtures thereof, preferably from bromine (Br), N-bromosuccinimide (NBS), and / or N-bromophthalimide.

[0075] Suitable acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0076] According to an embodiment, the compound of formula XI is prepared in the presence of an organic solvent, and suitable organic solvents are selected from the group consisting of C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas, and mixtures thereof.

[0077] According to another embodiment, the bromination of the compound of formula XII is carried out in the presence of a base, suitable bases being selected from the group consisting of alkali and alkaline earth hydroxides, hydrides, alkoxides and salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid and citric acid.

[0078] According to a preferred embodiment, the compound of formula XI is prepared in the presence of a base and an organic solvent.

[0079] According to another aspect of the present invention, a compound of formula I is prepared from a compound of formula XI, which is prepared as shown in Scheme 7 by: a) contacting a compound of formula XII with a brominating agent, optionally in the presence of a base and an organic solvent, to obtain a compound of formula XIII; and b) contacting a compound of formula XIII with an acid.

[0080] According to another aspect of the invention, a compound of formula XI is prepared by: a) contacting a compound of formula IV (wherein R is C-C alkyl, C-C alkoxy, C-C cycloalkyl, optionally substituted phenyl, or optionally substituted benzyl) with a base to obtain a compound of formula V, and b) contacting the compound of formula V with a pyridine of formula III (wherein L is a leaving group as defined above) in the presence of a base and an organic solvent, optionally in the presence of a catalyst, as shown in Scheme 8. [ka]

[0081] Scheme 8 Preparation of Compounds of Formula XI from Compounds of Formula IV Suitable bases are selected from the group consisting of alkali and alkaline earth hydroxides, hydrides, alkoxides and salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid and citric acid.

[0082] Suitable organic solvents are selected from the group consisting of C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas, and mixtures thereof.

[0083] According to an embodiment, the process is carried out in the presence of a catalyst selected from the group consisting of alkali fluorides such as CsF, KF, NaF, tetraethylammonium hydrogen sulfate, quaternary ammonium salts such as triethylbenzylammonium chloride, phosphonium salts such as tetraphenylphosphonium bromide, PEGs, crown ethers and mixtures thereof.

[0084] A suitable molar ratio of catalyst to pyrazole compound of formula V is from 0.001 to 100 mol / mol, especially from 0.01 to 10.0 mol / mol.

[0085] Another aspect of the invention relates to the preparation of compounds of formula I from compounds of formula XI prepared as shown in the previous embodiments.

[0086] According to an embodiment, the present invention provides compounds of formula I, in particular 3-bromo5-methyl-1-H-pyrazoline. The present invention relates to N-chloropyridine, its stereoisomers, solvates and / or N-oxides.

[0087] In another aspect of the invention, the compounds of formula I prepared by the process of the invention may be useful as intermediates for preparing the compound of formula VIII (chlorantraniliprole) by methods known from WO 2001 / 070671, WO 2006062978, WO 2003 / 015519 and WO 2003 / 015518.

[0088] According to additional aspects of the invention, compounds of formula VIII are prepared using a compound of formula II formed by contacting a compound of formula IV with a base to obtain a compound of formula V, and further decarboxylating the compound of formula V in the presence of an acid; or b) by contacting a compound of formula IV with an acid as disclosed above.

[0089] An additional aspect of the present invention is the preparation of a compound of formula VIII using a compound of formula XI formed by contacting a compound of formula VI with a brominating agent, optionally in the presence of a base and an organic solvent, as disclosed above.

[0090] An additional aspect of the present invention is the preparation of a compound of formula VIII using a compound of formula XI, as disclosed in the previous embodiment, which is formed by: a) contacting a compound of formula IV, wherein R is C-C alkyl, C-C alkoxy, C-C cycloalkyl, optionally substituted phenyl, or optionally substituted benzyl, with a base to obtain a compound of formula V; and b) contacting a compound of formula V, wherein L is a leaving group as defined above, with a pyridine of formula III in the presence of a base and an organic solvent, optionally in the presence of a catalyst.

[0091] An additional aspect of the present invention is the preparation of compounds of formula VII using compounds of formula I prepared by the methods disclosed above.

[0092] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are merely illustrative and are not intended to limit the disclosure in any way.

[0093] Example [Example]

[0094] Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (A) To a 500 mL four-neck flask equipped with a mechanical stirrer and thermometer, 152.7 g (1.20 mol) of 99% dimethyl sulfate was added and heated to 80°C. 92.9 g (1.26 mol) of DMF was added dropwise to the reaction at 80-90°C within 1 hour. The mixture was maintained at 80-85°C for 3 hours and then cooled to 20-30°C to obtain a DMF-DMS solution.

[0095] To a 1-liter four-neck flask equipped with a mechanical stirrer, thermometer, and dropping funnel, 131.3 g (1.0 mol) of 99% ethyl acetoacetate and 122.4 g (1.20 mol) of triethylamine were added. The DMF-DMS solution prepared above was added dropwise to the mixture over 30 minutes, and the temperature was maintained below 20°C. After the addition was complete, the reaction mixture was warmed to 25-30°C and stirred for an additional hour. 1 L of DCM and 0.5 L of water were added to the mixture and stirred for an additional 10 minutes. The aqueous layer was separated and extracted again with 2 x 200 mL of DCM. The combined ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate / DCM solution was used without further purification (yield: 99%). %). [Example]

[0096] Preparation of ethyl 3-methyl-1H-pyrazole-4-carboxylate (VI) A 1-liter four-neck flask equipped with a mechanical stirrer, thermometer, and dropping funnel was charged with ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate / DCM solution (1.0 mol). 65.6 g (1.05 mol) of 80% hydrazine hydrate was added dropwise to the DCM solution over 2 hours, maintaining the temperature below 20°C. The mixture was then heated to 25-30°C and stirred for an additional hour. The resulting DCM layer was separated and washed with 0.5% aqueous HCl until the pH of the aqueous phase was below 7. The DCM layer was concentrated to give 143 g of ethyl 3-methyl-1H-pyrazole-4-carboxylate as a yellow liquid (yield: 93%). [Example]

[0097] Preparation of ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate(IV) To a 2-L four-necked flask equipped with a mechanical stirrer, thermometer, pH meter, and dropping funnel, 143 g (0.93 mol) ethyl 3-methyl-1H-pyrazole-4-carboxylate, 250 mL of EtOH, 270 g of water, and 77.0 g (0.93 mol) of NaOAc were added, and the reaction mixture was stirred at room temperature for 0.5 h. 203 g (1.26 mol) of Br2 was added dropwise to the reaction mixture over 2 h, during which time 20% aqueous NaOH was added to maintain the pH between 6 and 8. The mixture was then stirred for an additional 1 h at 20–30°C. The resulting mixture was then filtered, and the filtrate was concentrated under vacuum (−0.1 MPa) at 40°C and then filtered again. The combined filter cake was stirred in 500 mL of water for 0.5 h. The mixture was filtered and washed with 500 mL of water, and the filter cake was dried to give 216.0 g of ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate as a white solid (98% yield). [Example]

[0098] Preparation of 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid (V) To a 100 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 3.2 g (80 mmol) of NaOH and 46 mL of HO were added. After the NaOH dissolved, 9.3 g (40 mmol) of ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate was added and suspended in the solution. The mixture was heated to 100°C and maintained at this temperature for 4 hours. The mixture was then cooled to 5 to 10°C and quenched with 10 mL of concentrated HCl. The resulting mixture was isolated by filtration, and the filter cake was washed with 10 mL of water and dried to give 8.2 g of 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid as a pale white solid (100% yield). [Example]

[0099] Preparation of 5-bromo-3-methyl-1H-pyrazole (II) To a 100 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser was added 8.2 g (40 mmol) of 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid and 67 mL (0.8 mol) of concentrated HCl. The mixture was heated to 105 °C and maintained at this temperature for 6 hours. After the reaction was complete, it was cooled to room temperature and concentrated to dryness. The residue was dissolved in 40 mL of water and neutralized with 6 mol / L aqueous NaOH solution to a pH of 7-8. The resulting mixture was isolated by filtration, and the filter cake was washed with 5 mL of water and dried to give 5.9 g of 5-bromo-3-methyl-1H-pyrazole as a pale white solid (92% yield). [Example]

[0100] Preparation of 5-bromo-3-methyl-1H-pyrazole (II) To a 2-L four-neck flask equipped with a mechanical stirrer, thermometer, and dropping funnel was added 216.0 g (0.91 mol) of 98% ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate and 557 g (2.27 mol) of 40% H2SO4. The mixture was stirred at 100-110 °C for 22 h and then cooled to 20-30 °C. 606 g of 30% aqueous NaOH was then added to neutralize the mixture until it reached a pH of 7-8. The resulting mixture was filtered between 40-50 °C, and the filter cake was washed with 250 mL of water and dried to give 139.6 g of 5-bromo-3-methyl-1H-pyrazole as a pale white solid (93% yield). [Example]

[0101] Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole (I) To a 100 mL three-necked flask equipped with a mechanical stirrer, thermometer, and condenser was added 14.5 g (87.6 mmol) of 97% 3-bromo-5-methyl-1H-pyrazole, 13.2 g (87.6 mmol) of 98% 2,3-dichloropyridine, 24.5 g (175.1 mmol) of powdered potassium carbonate, 0.51 g (8.76 mmol) of 99% anhydrous potassium fluoride, 2.34 g (8.76 mmol) of 99% 1,4,7,10,13,16-hexaoxacyclooctadecane, and 44 mL of N,N-dimethylacetamide. The reaction was heated to 150 °C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature and filtered through a pad of Celite to remove undissolved solids. The solids were washed with 10 mL of N,N-dimethylacetamide. The resulting brown solution was distilled under reduced pressure, collecting the 45°C fraction, and 40 mL of water and 20 mL of hexane were added to the residue. The mixture was vigorously stirred at 50°C for 1 hour and then cooled to room temperature. The product was isolated by filtration and then air-dried for 12 hours to give 20.1 g of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole as a brown solid (79% yield). [Example]

[0102] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (VII) A 250 mL four-necked flask equipped with a magnetic stirrer, thermometer, condenser, and oxygen inlet was charged with 13.6 g (50 mmol) of 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)-3-chloropyridine, 5.8 g (50 mmol) of N-hydroxysuccinimide, and 136 mL of acetic acid. The mixture was heated to 120 °C while oxygen was bubbled in, and HNO (1 mL) was added dropwise. The reaction was maintained at 120 °C for 6 hours. After completion of the reaction, it was cooled to room temperature and concentrated to dryness. The residue was dissolved in 2 mol / L aqueous NaOH solution and washed with 30 mL of ethyl acetate. The pH of the aqueous solution was adjusted to 1-2 with 32% HCl. The resulting mixture was isolated by filtration, and the filter cake was washed with 20 mL of water and dried to give 9.8 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid as an off-white solid (65% yield). [Example]

[0103] Preparation of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid (VII) To a 100 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser was added 2.2 g (8.1 mmol) of 99% 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole, 91 mg (0.4 mmol) of 99% tetraethylammonium hydrogen sulfate, 16 mL of tert-butyl alcohol, and 64 mL of water. The mixture was heated to 80°C, and 3.8 g (24 mmol) of KMnO4 was added to the reaction mixture at 80°C within 4 hours. The reaction was vigorously stirred at 80°C for an additional 6 hours and then cooled to ambient temperature. 2 mL of saturated sodium sulfite was then added, and the reaction mixture was filtered. The cake was washed with 5 mL of water and 10 mL of dichloromethane. The filtrate was extracted with dichloromethane (10 mL x 3). The organic phase was concentrated to dryness, and 0.55 g of the raw material, 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole, was recovered. The pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid, and the crude product was collected by filtration and air-dried for 2 hours to give 1.01 g of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid as a white product (40% yield). [Example]

[0104] Preparation of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid (VII) A 250 mL pressure reactor was charged with 109 g of acetic acid, 6 g (22 mmol) of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole, 4.3 g (37.1 mmol) of N-hydroxysuccinimide, 0.4 g (2.2 mmol) of cobalt(II) acetate, and 0.2 g (1.1 mmol) of manganese(II) acetate. Oxygen was introduced into the reactor to reach 20 bar at room temperature. The mixture was heated under stirring for 30 minutes. When the mixture temperature reached 100°C, the reactor was pressurized with oxygen to 40 bar, and the temperature was set to 110°C. The reaction was allowed to proceed for 6 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in 2 mol / L aqueous NaOH solution and washed with 30 mL of ethyl acetate. The aqueous phase was adjusted to pH 1-2 with concentrated HCl. The resulting mixture was filtered, and the filter cake was washed with 20 mL of water and dried to give 4.7 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid as an off-white solid (70% yield). [Example]

[0105] Preparation of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid (VII) To a 250 mL four-necked RBF equipped with a magnetic stirrer, thermometer, condenser, and oxygen inlet, 10 g of M-272 (0.037 mol), 8.45 g of N-hydroxysuccinimide (0.073 mol), and 100 mL of acetic acid (10 volume equivalents) were added. The reaction mixture was stirred at room temperature for 15-20 minutes and then heated to 110°C. Oxygen gas purging was initiated at 5 mL / min. At this point, 7.6 g of NaNO2 was added portionwise (5-10 parts) to the reaction mass (reddish gas was immediately evolved). Oxygen purging was continued, and the reaction mass was stirred at 110°C for 2 hours. After completion of the reaction, the oxygen flow was stopped, the reaction mass was cooled to room temperature, and the acetic acid was evaporated under reduced pressure. The residual mass was dissolved in 110 mL of 2 N NaOH solution and stirred at room temperature for 0.5 hours. The aqueous phase was extracted twice with 50 mL of ethyl acetate, and the organic layer was separated. The organic layer was concentrated to dryness to recover 5.0 g of the starting material, 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole. The pH of the aqueous layer was adjusted to 1 with concentrated hydrochloric acid, and the crude product was collected by filtration and air-dried for 2 hours to give 4.33 g of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid as a white product (39% yield). [Example]

[0106] Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole (I) In a 100 mL three-necked flask equipped with a mechanical stirrer, thermometer, and condenser, add 10 g (60.2 mmol) of 97% 3-bromo-5-methyl-1H-pyrazole, 9.0 g (60.2 mmol) of 98% 2,3-dichloropyridine, 16.6 g (120.4 mmol) of 2,3-dichloropyridine, and 10 g (60.2 mmol) of 97% 3-bromo-5-methyl-1H-pyrazole. ) powdered potassium carbonate and 30 mL of N,N-dimethylacetamide were added. The reaction was heated to 150 °C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature and filtered through a pad of Celite to remove undissolved solids, and the solids were washed with 10 mL of N,N-dimethylacetamide. The resulting brown solution was distilled under reduced pressure, collecting the 45 °C fraction, and to the residue was added 40 mL of water and 20 mL of hexane. The mixture was stirred vigorously at 50 °C for 1 hour and then cooled to room temperature. The product was isolated by filtration and then air-dried for 12 hours to give 12.3 g of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole as a brown solid (75% yield). [Example]

[0107] Preparation of ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate(IV) To a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer, and dropping funnel, 100 g (0.65 mol) of ethyl 3-methyl-1H-pyrazole-4-carboxylate, 200 mL of EtOH, and 250 g of water were added. The reaction mixture was stirred at room temperature for 0.5 h, and 160 g (1.0 mol) of Br was added dropwise to the reaction mixture over 2 h. The mixture was then stirred at 20-30 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure at 40 °C. The filter cake was stirred in 500 mL of water for 0.5 h. The mixture was filtered and washed with 500 mL of water, and the filter cake was dried to give 75.7 g of ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate as a white solid (50% yield). [Example]

[0108] Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole (I) To a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer, and dropping funnel was added 113.9 g (0.36 mol) of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid and 353 g (1.44 mol) of 40% H2SO4. The mixture was stirred at 100-110 °C for 22 hours and then cooled to 20-30 °C. 380 g of 30% aqueous NaOH was added to neutralize the mixture until the pH reached 7-8. The resulting mixture was filtered at a temperature between 40 and 50 °C, and the filter cake was washed with 250 mL of water and dried to yield 63.6 g of a pale white solid. [Example]

[0109] Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (XIII) To a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, pH meter, and dropping funnel, 66.4 g (0.25 mol) of ethyl 1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate, 50 mL of EtOH, 70 g of water, and 20.7 g (0.25 mol) of sodium acetate were added. The reaction mixture was stirred at room temperature for 0.5 hours, and 50.4 g (0.32 mol) of Br was added dropwise to the reaction mixture over 2 hours, after which 20% aqueous NaOH was added to maintain the pH at 6-8. The mixture was then stirred at 20-30 °C for an additional 1 hour. The resulting mixture was then filtered, and the filtrate was concentrated under reduced pressure at 40 °C and then filtered again. The combined filter cake was stirred in 100 mL of water for 0.5 hours. The mixture was filtered and washed with 100 mL of water, and the filter cake was dried to give 84.4 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as a white solid. [Example]

[0110] Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (XIII) To a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and dropping funnel, 66.4 g (0.25 mol) of ethyl 1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate, 50 mL of EtOH, and 70 g of water were added, and the reaction mixture was stirred at room temperature for 0.5 h. 40 g (0.25 mol) of Br2 was added dropwise to the reaction mixture over 2 h, after which the mixture was stirred at 20-30 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure at 40 °C. The filter cake was stirred in 100 mL of water for 0.5 h. The mixture was filtered and washed with 100 mL of water, and the filter cake was dried to give 63.8 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as a white solid. [Example]

[0111] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (XI) To a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer, and dropping funnel, 50 g (0.15 mol) of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate and 0.75 L of 1 M HCl solution were added, and the mixture was heated to 110° C. and maintained for 5 hours. After the reaction was complete, the product was collected by filtration and dried to give 42.7 g of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid as a white solid. [Example]

[0112] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (XI) To a 100 mL three-necked flask equipped with a mechanical stirrer, thermometer, and condenser was added 5 g (24.4 mmol) of 3-bromo-5-methyl-1H-pyrazole-4-carboxylic acid, 3.61 g (24.4 mmol) of 98% 2,3-dichloropyridine, 6.77 g (49 mmol) of potassium carbonate powder, 0.14 g (2.44 mmol) of 99% anhydrous potassium fluoride, 0.65 g (2.44 mmol) of 99% 1,4,7,10,13,16-hexaoxacyclooctadecane, and 20 mL of N,N-dimethylacetamide. The reaction was heated to 150 °C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature and filtered through a pad of Celite to remove undissolved solids. The solids were washed with 10 mL of N,N-dimethylacetamide. The resulting brown solution was distilled under reduced pressure, and the 45°C fraction was collected and stirred with 20 mL of water and 10 mL of hexane at 50°C for 1 hour, then cooled to room temperature. The product was isolated by filtration and air-dried for 12 hours to give 6.18 g of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid as a brown solid. [Example]

[0113] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (XI) To a 100 mL three-necked flask equipped with a mechanical stirrer, thermometer, and condenser was added 5 g (24.4 mmol) of 3-bromo-5-methyl-1H-pyrazole-4-carboxylic acid, 3.61 g (24.4 mmol) of 98% 2,3-dichloropyridine, 6.77 g (49 mmol) of powdered potassium carbonate, and 20 mL of N,N-dimethyl-acetamide. The reaction was heated to 150 °C and vigorously stirred for 13 hours. The reaction was cooled to ambient temperature and filtered through a pad of Celite to remove undissolved solids. The solids were washed with 10 mL of N,N-dimethyl-acetamide. The resulting brown solution was distilled under reduced pressure, and the 45 °C fraction was collected. 20 mL of water and 10 mL of hexane were added to the residue, and the mixture was vigorously stirred at 50 °C for 1 hour, then cooled to room temperature. The product was isolated by filtration and then The solid was air-dried at rt for 12 hours to give 4.94 g of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid as a brown solid.

[0114] Additionally, any and all priority document(s) to this application are incorporated herein by reference in their entirety.

Claims

1. Formula II 【Chemical 1】 with a compound of formula III 【Chemistry 2】 where L is a leaving group. with pyridine of formula I in the presence of a base and an organic solvent, optionally in the presence of a catalyst 【Chemistry 3】 A method for preparing the compound of formula (I).

2. 2. The method of claim 1, wherein L is a halogen or an optionally halogenated sulfonyl group. Law.

3. 2. The method of claim 1, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and alkali metal salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid, and citric acid.

4. 2. The method of claim 1, wherein the organic solvent is selected from the group consisting of C1-C6 alcohols, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylethanolamine, 1-C6 alkanes, C1-C6 halogenated alkanes, benzene, toluene, chlorobenzene, xylene, nitrobenzene, 1,4-dioxane, and mixtures thereof.

5. 10. The method of claim 1, wherein the compound of formula I is prepared in the presence of a catalyst.

6. 10. The method of claim 1, wherein the catalyst is selected from the group consisting of alkali fluorides, quaternary ammonium salts, phosphonium salts, PEGs, crown ethers, and mixtures thereof.

7. 2. The process of claim 1 wherein the catalyst is selected from the group consisting of cesium fluoride, potassium fluoride, sodium fluoride, tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetraphenylphosphonium bromide, and mixtures thereof.

8. a) Formula IV 【Chemistry 4】 In the formula, R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy. phenyl, optionally substituted phenyl or optionally substituted benzyl by contacting a compound of formula V with a base 【Chemistry 5】 and further decarboxylating the compound of formula V in the presence of an acid; or b) contacting the compound of formula IV with an acid to obtain a compound of formula II; Formula II comprising 【Chemistry 6】 A method for preparing the compound of formula (I).

9. 9. The method of claim 8, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and alkali metal salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid, and citric acid.

10. 9. The method of claim 8, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, and mixtures thereof.

11. Formula XI 【Chemistry 8】 in the presence of an acid. 【Chemistry 9】 A method for preparing the compound of formula (I).

12. 12. The method of claim 11, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, and mixtures thereof.

13. a) Formula XII 【Chemistry 10】 is contacted with a brominating agent, optionally in the presence of a base and an organic solvent, to give a compound of formula XIII 【Chemistry 11】 wherein R is according to claim 8 and b) contacting a compound of formula XIII with an acid; 【Chemistry 12】 A method for preparing the compound of formula (I).

14. 14. The method of claim 13, wherein the compound of formula XI is prepared in the presence of a base.

15. 14. The method of claim 13, wherein the compound of formula XI is prepared in the presence of an organic solvent.

16. 14. The method of claim 13, wherein the compound of formula XI is prepared in the presence of a base and an organic solvent.

17. 17. The method of any one of claims 13 and 16, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and alkali metal salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid, and citric acid.

18. 17. Any of claims 13 to 16, wherein the organic solvent is selected from the group consisting of C1-C6 alcohols, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylethanolamine, 1-C6 alkanes, C1-C6 halogenated alkanes, benzene, toluene, chlorobenzene, xylene, nitrobenzene, 1,4-dioxane, and mixtures thereof.

2. The method according to claim 1.

19. 14. The method of claim 13, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, and mixtures thereof.

20. 14. The method of claim 13, wherein the brominating agent is selected from the group consisting of bromine (Br2), N-bromosuccinimide (NBS), dibromodimethylhydantoin, N-bromophthalimide, N-bromosaccharin, monosodium bromoisocyanurate hydrate, dibromoisocyanuric acid (=DBI), bromodimethylsulfonium bromide, 5,5-dibromoMeldrum's acid CAS RN: 66131-14-4, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate, and BrCl, and mixtures thereof.

21. 14. The method of claim 13, wherein the brominating agent is selected from bromine (Br2), N-bromosuccinimide (NBS), and / or N-bromophthalimide.

22. a) Formula IV 【Chemistry 13】 In the formula, R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy. phenyl, optionally substituted phenyl or optionally substituted benzyl; is contacted with a base to form a compound of formula V 【Chemistry 14】 and b) reacting a compound of formula V with a compound of formula III 【Chemistry 15】 where L is a leaving group. with pyridine of formula XI in the presence of a base and an organic solvent, optionally in the presence of a catalyst. 【Chemistry 16】 A method for preparing the compound of formula (I).

23. 23. The method of claim 22, wherein the base is selected from the group consisting of alkali and alkaline earth metal hydroxides, hydrides, alkoxides, and alkali metal salts of sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, formic acid, oxalic acid, carbonic acid, acetic acid, propionic acid, benzoic acid, and citric acid.

24. 23. The method of claim 22, wherein the organic solvent is selected from the group consisting of C1-C6 alcohols, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylethanolamine, 1-C6 alkanes, C1-C6 halogenated alkanes, benzene, toluene, chlorobenzene, xylene, nitrobenzene, 1,4-dioxane, and mixtures thereof.

25. 23. The method of claim 22, wherein the catalyst is selected from the group consisting of alkali fluorides, quaternary ammonium salts, phosphonium salts, PEGs, crown ethers, and mixtures thereof.

26. 23. The method of claim 22, wherein the catalyst is selected from the group consisting of cesium fluoride, potassium fluoride, sodium fluoride, tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetraphenylphosphonium bromide, and mixtures thereof.

27. Formula I: 【Chemistry 17】 Compound.

28. Formula I 【change】 with an oxidant, optionally in the presence of a catalyst. 【Chemistry 18】 A method for preparing the compound of formula (I).

29. 29. The method of claim 28, wherein the oxidant is selected from the group consisting of oxygen, air, ozone, hydrogen peroxide, benzoyl peroxide, tert-butyl peroxide, m-chloroperbenzoic acid, peracetic acid, perbenzoic acid, magnesium monoperoxyphthalate, potassium peroxymonosulfate, sodium permanganate, potassium permanganate, and mixtures thereof.

30. 29. The process of claim 28 in the presence of a catalyst selected from the group consisting of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetraphenylphosphonium bromide, PEGs, crown ethers, sodium nitrite, tert-butyl nitrite, cobalt(II) acetate, manganese(II) acetate, and mixtures thereof.

31. 29. The process of claim 28 in the presence of N-hydroxysuccinimide, N-hydroxyphthalimide, and a catalyst selected from the group consisting of sodium nitrite, tert-butyl nitrite, cobalt (II) acetate, manganese (II) acetate, and mixtures thereof.

32. The following steps: a) Formula I 【change】 is reacted with an oxidant, optionally in the presence of a catalyst, to give a compound of formula VII 【Chemical Formula 28】 to obtain a compound of formula (I): b) reacting a compound of formula VII with an ortho-aminoaromatic carboxylic acid IX 【Chemistry 20】 to give the corresponding benzoxazinone X 【Chemical 21】 and c) reacting the resulting benzoxazinone X with methylamine to give the compound of formula VIII 【Chemical 22】 to obtain a compound of formula (I):

10. A process for preparing a compound of formula VIII, comprising:

33. The following steps: a) Formula I 【change】 is reacted with an oxidant, optionally in the presence of a catalyst, to give a compound of formula VII 【Chemical 29】 to obtain a compound of formula (I): b) reacting a compound of formula VII with an anthranilic acid amide XI 【Chemical 23】 to obtain a compound of formula VIII; Formula VIII comprising 【Chemistry 24】 A method for preparing the compound of formula (I).

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