Method for preparing carboxylic acid derivatives of 3-bromo-4,5-dihydro-1H-pyrazole

Abstract

Compounds of formula (I) and (II) [Formula 1] TIFF2022545773000022.tif63170 (in the formula, R 1 , R 2 , R 3 , X and n are as defined in this disclosure.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 888,667, filed August 19, 2019, and U.S. Provisional Patent Application No. 62 / 890,154, filed August 22, 2019, the disclosures of which are incorporated by reference in their entireties herein.

[0002] The present disclosure relates to the preparation of 3-halo-4,5-dihydro-1H-pyrazoles using a novel one-step bromination process. The compounds prepared by the methods disclosed herein are useful for the preparation of certain anthranilamide compounds that are of interest as insecticides. [Background technology]

[0003] Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate is an intermediate in the preparation of anthranilamides, such as the insecticides chlorantraniliprole and cyantraniliprole. The preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate from ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate in a two-step process is described in US Pat. No. 5,399,433 to DuPont. In the first step, ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate is treated with benzenesulfonyl chloride to give ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate. In the second step, ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazole-5-carboxylate is treated with a solution of hydrogen bromide in acetic acid to give ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate in 86% overall yield. Alternative methods for the preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate from ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate have also been described, such as a one-step bromination process using phosphoric acid oxybromide (POBr3) or phosphorus pentabromide (PBr5). However, POBr3 and PBr5 are not commercially available on the scale required for the preparation of anthranilamide compounds. PBr5 may be the cheapest to produce, but it has a tendency to agglomerate into hard solid blocks, making it difficult to transport and store. One way to circumvent this problem is by preparing PBr5 in situ by reacting PBr3 with bromine (Patent Document 2).Both PBr3 and bromine are commercially available in sufficient quantities. In this option, PBr3 is treated with bromine to obtain a slurry of PBr5 to which ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate is added. However, one of the drawbacks of this method is that PBr5 tends to coat the walls of the reactor in which it is formed, making it difficult to transfer the mixture to another reactor. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 6,965,032 [Patent Document 2] Chinese Patent Application No. 102399211A Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure provides novel processes useful for preparing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate and its derivatives in a convenient and cost-effective manner. [Means for solving the problem]

[0006] Compounds of formula (I) [ka] (In the formula, R 1 is a halogen; 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 CR4; R 4 But H or R 2 and; n is 0, 1, 2, or 3, provided that when X is CH, then n is at least 1. (1) a method for preparing a compound of formula (A) [ka] (In the formula, X, R 2 and n is as described above for formula (I), R 3 is C1-C4 alkyl) with phosphorus tribromide (PBr3); and (2) treating the resulting product with bromine (Br2); and obtaining a compound of formula (I), 3 is H), (3) The compound formed in (2) is reacted with a compound (wherein R 3 is H).

[0007] Compound of formula (II) [ka] (In the formula, R1 is halogen) (and X, R 2 , R 3 and n are as described above for formula (I). The method includes (4) treating a compound of formula (A) according to the steps described above to form a compound of formula (I); and 3 is C1-C4 alkyl) to prepare a compound of formula (II) 3 is H), the compound formed in (5)(3) is converted to a compound of formula (II), 3 is H). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] In the above description, the term "alkyl", used alone or in compounds such as "alkylthio" or "haloalkyl", includes linear or branched alkyls, such as methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" may include linear 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. "Alkynyl" includes linear or branched alkynes, such as 1-propynyl, 2-propynyl, and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" may also include moieties consisting of multiple triple bonds, such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the different butoxy, pentoxy, and hexyloxy isomers. "Alkoxyalkyl" refers to alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CHOCH, CHOCHCH, CHCHOCH, CHCHCHOCH, and CHCHOCHCH. "Alkylthio" includes branched or straight chain alkylthio moieties, such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, and hexylthio isomers. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group, including, for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl, and cyclohexylmethyl. "Cycloalkylamino" means that the amino nitrogen atom is bound to a cycloalkyl group 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 is replaced by an alkyl group; examples include groups such as (alkyl)cyclopropylamino, (alkyl)cyclobutylamino, (alkyl)cyclopentylamino and (alkyl)cyclohexylamino. Preferably, the alkyl in (alkyl)cycloalkylamino is C1-C4 alkyl, while the cycloalkyl in cycloalkylamino and (alkyl)cycloalkylamino is C3-C6 cycloalkyl.

[0009] The term "aryl" in this application 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 indicates that each of the ring atoms is essentially in the same plane, has p-orbitals perpendicular to the plane of the ring, and (4n+2) π electrons are bonded to the ring in accordance with the Huckel 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 fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic and at least one ring atom is not carbon and may contain 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heteroaromatic ring contains up to 4 nitrogens, up to 2 oxygens and up to 2 sulfurs (where aromatic indicates that Huckel's rule is satisfied). The heterocyclic ring system may be linked through any available carbon or nitrogen by replacement of hydrogen at said carbon or nitrogen. More specifically, the term "aryl" refers to the moiety. [ka] In the formula, R 2 and n is defined as above, and the "3" indicates the 3-position of the substituent on the moiety.

[0010] The term "halogen", alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Furthermore, when used in compound words 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. Terms such as "haloalkenyl", "haloalkynyl", "haloalkoxy" 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.

[0011] Examples of "alkylcarbonyl" include C(O)CH3, C(O)CH2CH2CH3, and C(O)CH(CH3). Examples of "alkoxycarbonyl" include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O) and the different butoxy- or pentoxycarbonyl isomers. The terms "alkylaminocarbonyl" and "dialkylaminocarbonyl" include, for example, CH3NHC(=O), CH3CH2NHC(=O), and (CH3)2NC(=O).

[0012] The total number of carbon atoms in the substituent is "C i ~C j " (where i and j are numbers from 1 to 8). For example, C1-C3 alkylsulfonyl denotes methylsulfonyl to propylsulfonyl. In the above description, when the compound of formula (I) contains a heteroaromatic ring, all substituents are attached to this ring through any available carbon or nitrogen by replacement of a hydrogen at said carbon or nitrogen.

[0013] The group may be hydrogen, e.g. R 4When a group includes a substituent which may be, when that substituent is taken to be hydrogen, it will be recognised that this is equivalent to said group being unsubstituted.

[0014] 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 appreciate that one stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to or separated from other stereoisomers. Furthermore, those skilled in the art will recognize methods to separate, enrich and / or selectively prepare said stereoisomers. Thus, embodiments of the present disclosure include:

[0015] Embodiment 1. A method of preparing a compound of formula (I) wherein n is 1, 2, or 3.

[0016] The method of embodiment 1, wherein n is 1.

[0017] Embodiment 3.R 1 3. The method of embodiment 1 or 2, wherein is Cl or Br.

[0018] Embodiment 4.R 1 The method of any one of embodiments 1 to 3, wherein is Br.

[0019] Embodiment 5. Each R 2 is independently Cl or Br, and one R 2 The method of any one of embodiments 1 to 4, wherein is at position 3.

[0020] Embodiment 6. Each R 2 The method of any one of the preceding embodiments, wherein is Cl at the 3 position.

[0021] Embodiment 7.R 3 The method of any one of the preceding embodiments, wherein is C1-C4 alkyl.

[0022] Embodiment 8.R 3 The method of any one of embodiments 1-7, wherein is Et.

[0023] Embodiment 9. The method of any one of embodiments 1 to 8, wherein X is N.

[0024] Embodiment 10. The method of any one of embodiments 1 to 10, wherein the method is carried out in the presence of a solvent.

[0025] Embodiment 11. The method of embodiment 10, wherein the solvent is selected from acetonitrile, N,N-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobenzene, tetrachloromethane, dichlorobenzene, dichloromethane, and 1,2-dichloroethane.

[0026] Embodiment 12. The method of embodiment 11, wherein the solvent is selected from acetonitrile, chlorobenzene, dichloromethane, and 1,2-dichloroethane.

[0027] Embodiment 13. The method of embodiment 11 or 12, wherein the solvent is acetonitrile.

[0028] Embodiment 14. The method of any one of embodiments 1 to 13, further comprising treating the product after step (2) with a base.

[0029] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the base is selected from solid sodium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, ammonium bicarbonate, trisodium phosphate, tripotassium phosphate, cesium carbonate, triethylamine, pyridine, N-methylimidazole, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, and potassium hydroxide.

[0030] Embodiment 16. The method of any one of embodiments 14-15, wherein the base is selected from solid sodium bicarbonate, potassium carbonate, and sodium carbonate.

[0031] Embodiment 17. The method of any one of embodiments 14-16, wherein the base is solid sodium bicarbonate.

[0032] Embodiment 18. The method of embodiment 17, further comprising treating the product with solid sodium bicarbonate followed by adding water.

[0033] Embodiment 19. The method of any one of embodiments 14-16, wherein the base is a saturated sodium bicarbonate solution.

[0034] Embodiment 20. The method of embodiment 19, further comprising treating the product with saturated sodium bicarbonate solution followed by adding solid sodium bicarbonate.

[0035] Embodiment 21. The method of any one of embodiments 14-16, wherein the base is a sodium carbonate solution.

[0036] Embodiment 22. The method of any one of embodiments 14 to 16, wherein the base is a potassium carbonate solution.

[0037] Embodiment 23. The method of any one of embodiments 1 to 22, further comprising isolating the compound of formula (I).

[0038] Embodiment 24. The method of any one of embodiments 1 to 23, wherein the compound of formula (I) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate.

[0039] Embodiment 25. A method of preparing a compound of formula (II) wherein n is 1, 2, or 3.

[0040] Embodiment 26.R 126. The method of embodiment 25, wherein is Cl or Br.

[0041] Embodiment 27.R 2 The method of any one of embodiments 25-26, wherein is independently Cl or Br.

[0042] 28. One R 2 28. The method of embodiment 27, wherein:

[0043] Embodiment 29.R 3 The method of any one of embodiments 25-28, wherein is C1-C4 alkyl.

[0044] Embodiment 30. The method of any one of embodiments 25 to 29, wherein X is N.

[0045] Embodiment 31. The method of any one of embodiments 25-30, further comprising isolating the compound of formula (II).

[0046] Embodiment 32. The method of any one of embodiments 25 to 30, wherein the compound of formula (II) is ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate.

[0047] Embodiment 33. The method of any one of embodiments 1 to 32, wherein steps (1) and (2) are independently carried out at a temperature between 15° C. and 50° C. In one embodiment, useful temperatures at which steps (1) and (2) may be carried out include 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., and 50° C.

[0048] Embodiment 34. The compound of formula (I) has the following structure: [ka] and the compound of formula (A) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate having the structure: [ka] The method of any one of the preceding embodiments, wherein the compound is ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate having the formula:

[0049] Stepwise methods for preparing compounds of formula (I) and formula (II) are described below.

[0050] Methods for preparing compounds of formula (A) are known in the art and are described, for example, in US Pat. No. 6,965,032 B2.

[0051] The process for preparing compounds of Formula (I) and Formula (II) provided herein includes the steps of: (1) reacting a compound of Formula (A) in the presence of a solvent; [ka] (In the formula, X, R 2 and n is as defined above, R 3 is H; or R 3 is C1-C4 alkyl) with PBr3. The resulting product is then (2) treated with bromine to give the compound of formula (I); [ka] (In the formula, X, R 1 , R 2 and n is as defined above, R 3 is H; or R 3 is C1-C4 alkyl).

[0052] Due to the excess bromine, a certain amount of the compound of formula (I) is oxidized to the compound of formula (II) [ka] (In the formula, X, R 1 , R 2and n is as defined above, R 3 is H; or R3 is C1-C4 alkyl.

[0053] Scheme 1 illustrates steps (1) and (2) in more detail. The compound of formula (A) is first (1) treated with PBr3 in the presence of a solvent. Useful solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobenzene, tetrachloromethane, dichlorobenzene, dichloromethane, or 1,2-dichloroethane. In one embodiment, the solvent is selected from acetonitrile, chlorobenzene, dichloromethane, and 1,2-dichloroethane. In one embodiment, acetonitrile is used as the solvent. The resulting product is then (2) treated with bromine to obtain a slurry of the hydrobromide salt of the compound of formula (I). [ka]

[0054] The reaction mass is then treated with an inorganic base including, but not limited to, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, ammonium bicarbonate, trisodium phosphate, tripotassium phosphate, cesium carbonate, triethylamine, pyridine, N-methylimidazole, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, or potassium hydroxide. In one embodiment, the reaction mass is treated with solid sodium bicarbonate and then water is added to dissolve the solids. In one embodiment, the reaction mass is treated with saturated sodium bicarbonate solution followed by solid sodium bicarbonate to complete the neutralization. In one embodiment, the reaction mass is neutralized by adding a sodium carbonate solution or a potassium carbonate solution.

[0055] Optionally, the desired product, the compound of formula (I), may be isolated by methods known to those skilled in the art, including, but not limited to, crystallization, extraction, and distillation. Using the methods disclosed herein, a yield of about 90-95% of the compound of formula (I) is achieved. It is noteworthy that in addition to the compound of formula (I), the described method yields about 1%-5% of the compound of formula (II). It should be noted that this method avoids the formation of PBr5.

[0056] Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent using the above description. Thus, the following examples should be construed as merely illustrative and in no way limiting of the present disclosure. The starting materials for the following examples may not necessarily have been prepared according to the specific preparation examples whose procedures are described in other examples. Percentages are by weight, except for chromatography solvent mixtures or unless otherwise indicated. Parts and percentages for chromatography solvent mixtures are by volume, unless otherwise indicated. Any numerical range recited herein is also understood to include all values ​​from the lower limit to the upper limit. For example, if a range is recited as 10-50, values ​​such as 12-30, 20-40, or 30-50 are intended to be expressly recited herein. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​between the lowest and highest values ​​(including the lowest and highest values) are considered to be expressly recited in this application.

[0057] 1 H NMR spectra are reported in ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "dd" means doublet of doublets, "dt" means doublet of triplets, and "br s" means broad singlet. All reagents described in the following examples are available from commercial sources. EXAMPLES

[0058] Example 1 Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate using solid sodium bicarbonate for neutralization * and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate ** Preparation of 150 g of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate was treated with 90.3 g of phosphorus tribromide (PBr3) in 750 ml of acetonitrile at 30-50° C. for 0.5 hours. The mixture is then treated with 53.3 g of bromine (Br2) at 30-40° C. The reaction product was heated to reflux (at about 83° C., which can be carried out at about 80° C. to about 83° C.) for 1-2 hours. After the reaction was complete, the resulting ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate-HBr slurry was treated portionwise with 140 g of solid sodium bicarbonate. The mixture was then diluted by adding 600 g of water portionwise. The biphasic mixture was adjusted to pH 7-8 and the phases were separated. The organic phase was concentrated under reduced pressure to remove acetonitrile. The residue was mixed with 120 g of EtOH and 150 g of water. The resulting slurry was filtered to give 173.7 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (98.1 wt %), corresponding to a 92% yield. Due to the presence of excess bromine, a portion of the ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate was further oxidized to produce ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, corresponding to a yield of about 1.0% to 5.0%.

[0059] It should be noted that neutralization with solid bicarbonate is often not complete due to the inclusion of sodium bicarbonate by the reaction product. The addition of a phase transfer catalyst is often required. Surprisingly, in this case, the neutralization reaction is complete without a phase transfer catalyst. Therefore, it is expected that any method of producing ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate-HBr slurry can similarly benefit from the addition of solid bicarbonate as disclosed herein.

[0060] Example 2 (Listed as a comparative example) Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate prepared in situ using PBr5 * Preparation of In this example, PBr5 was prepared in situ by reacting PBr3 with bromine. Then, ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate was added to the PBr5 slurry. Specifically, 81 g of PBr3 and 48 g of Br2 were mixed in 1490 mL of acetonitrile at 20° C. for 2 hours. The resulting PBr5 slurry was then treated with 68 g of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate, and the mixture was heated to 80° C. for 2 hours. After the reaction was completed, the solvent was removed under pressure. The residue was dissolved in dichloromethane, and the solution was washed with water. The organic phase was concentrated to give 82.1 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (90% by weight), corresponding to a yield of 88%.

[0061] Example 3 Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate using sodium bicarbonate solution and solid sodium bicarbonate for neutralization *and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate ** Preparation of 135 g of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate was treated with 74.4 g of phosphorus tribromide (PBr3) in 675 ml of acetonitrile at 30-50° C. for 0.5 hours. The mixture is then treated with 43.9 g of bromine (Br2) at 30-40° C. The reaction product was heated to reflux (at about 83° C.) for 1-2 hours. After the reaction was complete, the resulting ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate-HBr slurry was treated portionwise with 720 g of sodium bicarbonate solution in water (50 g of solid sodium bicarbonate was dissolved in 675 g of water), and then an additional 65 g of solid sodium bicarbonate was added portionwise. The biphasic mixture was adjusted to pH 7-8 and the phases were separated. The organic phase was concentrated under reduced pressure to remove acetonitrile. The residue was mixed with 106 g of EtOH and 135 g of water. The resulting slurry was filtered to give 155 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (98.0 wt %), corresponding to a yield of 91%. Due to the presence of excess bromine, a portion of the ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate was further oxidized to produce ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, corresponding to a yield of about 1.0% to 5.0%.

[0062] Example 4 Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate using sodium carbonate solution and solid sodium carbonate for neutralization * and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate ** Preparation of 135 g of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate was treated with 74.4 g of phosphorus tribromide (PBr3) in 675 ml of acetonitrile at 30-50 °C for 0.5 hours. The mixture is then treated with 43.9 g of bromine (Br2) at 30-40 °C. The reaction product was heated to reflux (at about 83 °C) for 1-2 hours. After the reaction was complete, the resulting ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate-HBr slurry was treated portionwise with 748 g of sodium carbonate solution in water (73 g of solid sodium carbonate was dissolved in 675 g of water). The biphasic mixture was adjusted to pH 7-8 and the phases were separated. The organic phase was concentrated under reduced pressure to remove acetonitrile. The residue was mixed with 106 g of EtOH and 135 g of water. The resulting slurry was filtered to obtain 152 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (98.5 wt%), corresponding to a yield of 90%. Due to the presence of excess bromine, a portion of the ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate was further oxidized to produce ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, corresponding to a yield of about 1.0% to 5.0%.

[0063] Example 5 Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate using potassium carbonate solution and solid potassium carbonate for neutralization * and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate ** Preparation of 135 g of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate was treated with 74.4 g of phosphorus tribromide (PBr3) in 675 ml of acetonitrile at 30-50 °C for 0.5 hours. The mixture is then treated with 43.9 g of bromine (Br2) at 30-40 °C. The reaction product was heated to reflux (at about 83 °C) for 1-2 hours. After the reaction was complete, the resulting ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate-HBr slurry was treated portionwise with 768 g of potassium carbonate solution in water (93 g of solid potassium carbonate was dissolved in 675 g of water). The biphasic mixture was adjusted to pH 7-8 and the phases were separated. The organic phase was concentrated under reduced pressure to remove acetonitrile. The residue was mixed with 106 g of EtOH and 135 g of water. The resulting slurry was filtered to obtain 155 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (98.3 wt%), corresponding to a yield of 92%. Due to the presence of excess bromine, a portion of the ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate was further oxidized to produce ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, corresponding to a yield of about 1.0% to 5.0%. *1 H NMR (DMSO-d6, 400MHz) δ=1.12(t,J=7.0Hz, 3H), 3.24-3.31(m,1H), 3.54-3.61(m,1H), 4.08(q,J=7.0Hz) , 2H), 5.14-5.19(m,1H), 6.98(dd,J=4.8Hz, J=7.6Hz, 1H), 7.83(d,J=7.7Hz, 1H), 8.10(d,J=4.4Hz, 1H). **1H NMR((DMSO-d6, 400MHz)δ=1.20(t,J=7.2Hz, 3H), 4.23(q,J=7.2Hz, 2H), 6.94(s,1 H), 7.44(dd,J=4.8Hz, J=8.1Hz, 1H), 7.91(d,J=8.1Hz, 1H), 8.51(d,J=4.8Hz, 1H).

[0064] By the procedures described herein together with methods known in the art, the following compounds in Tables 1-3 may be prepared. The following abbreviations are used in the tables: t is tertiary, s is secondary, n is normal, i is iso, Me is methyl, Et is ethyl, Pr is propyl, i-Pr is isopropyl, and t-Bu is tertiary butyl.

[0065] [Table 1]

[0066] [Table 2]

[0067] [Table 3]

[0068] usefulness The compounds of formula (I), (II) and (A) may be prepared by reacting the compounds of formula (III) [ka] (In the formula, X, R 1 , R 2 and n is defined as above; R 6 is CH3, Cl or Br; R 7 is CN, F, Cl, Br, I or CF3; R 8 is C1-C4 alkyl).

[0069] The compounds of formula (III) are useful as insecticides.

[0070] Compounds of formula (III) can be prepared from compounds of formula (II) and thus from compounds of formula (A) and (I) by the methods already disclosed in US Pat. No. 6,965,032 B2.

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, R 1 is a halogen; Each R 2 But independently, C 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, provided that if X is CH, then n is at least 1. A method for preparing (a) A compound of formula (A) 【Chemistry 2】 (In the formula, R 3 But, C 1 ~C 4 with phosphorus tribromide; (b) treating the product from step (a) with bromine; and compounds of formula (I), 3 is H, the compound formed in (a) can be prepared by reacting the compound 3 wherein

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

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

4. R 2 The method of any one of claims 1 to 3, wherein is independently Cl or Br.

5. One R 2 The method of claim 4 , wherein:

6. R 3 But, 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 X is N.

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

9. 9. The method of any one of claims 1 to 8, wherein steps (a) and (b) are independently carried out at a temperature of from 15°C to 50°C.

10. The process according to any one of claims 1 to 9, wherein the process is carried out in the presence of a solvent.

11. 11. The method of claim 10, wherein the solvent is selected from acetonitrile, N,N-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobenzene, tetrachloromethane, dichlorobenzene, dichloromethane, and 1,2-dichloroethane.

12. The method according to claim 10 or 11, wherein the solvent is selected from acetonitrile, chlorobenzene, dichloromethane, and 1,2-dichloroethane.

13. The method according to any one of claims 10 to 12, wherein the solvent is acetonitrile.

14. 14. The process of any one of claims 1 to 13, further comprising: (c) treating the product obtained from step (b) with a base.

15. 15. The method of claim 14, wherein the base is selected from solid sodium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, ammonium bicarbonate, trisodium phosphate, tripotassium phosphate, cesium carbonate, triethylamine, pyridine, N-methylimidazole, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, and potassium hydroxide.

16. 16. The method of claim 14 or 15, wherein the base is selected from solid sodium bicarbonate, saturated sodium bicarbonate, sodium carbonate, and potassium carbonate.

17. The process according to any one of claims 14 to 16, wherein the base is solid sodium bicarbonate.

18. 20. The method of claim 17, further comprising adding water after treating the product resulting from step (b) with solid sodium bicarbonate.

19. Compound of formula (II) 【Chemistry 5】 (In the formula, R 1 is a halogen; Each R 2 But independently, C 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 if X is CH, then n is at least 1. The method according to any one of claims 1 to 18 for preparing

20. The compound of formula (II) has the following structure: 【Chemistry 6】 20. The method of claim 19, wherein the compound is ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate having the formula:

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