PROCESS FOR THE PREPARATION OF 3-BROMO-4,5-DIHYDRO-1H-PYRAZOLE CARBOXYLIC ACID DERIVATIVES

Abstract

A method for preparing a compound of Formula (I) and (II) (see Formulas) is disclosed, where R1, R2, R3, X and n are as defined in the disclosure.

Description

PROCESS FOR THE PREPARATION OF 3-BROMO-4,5-DIHYDRO-1H-PYRAZOLE CARBOXYLIC ACID DERIVATIVES CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. provisional application no. B62 / 888 667, filed on August 19, 2019, and U.S. provisional application no. s62 / 890 154, filed on August 22, 2019, the disclosures of which are incorporated herein by reference in their entirety. FIELD This 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 process disclosed herein are useful for the preparation of certain anthranilamide-type compounds that are of interest as insecticides. BACKGROUND Ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / - / -pyrazol-5-carboxylate is an intermediate in the preparation of anthranilamides such as, for example, the insecticides chlorantraniliprole and cyantraniliprole. The preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate from ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1 / - / -pyrazol-5-carboxylate in a two-step process is described in U.S. Patent No. 6,965,032 to DuPont. In the first step, ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1 / 7-pyrazol-5-carboxylate is treated with benzenesulfonyl chloride to obtain ethyl 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate.In the second step, 1-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-1H-pyrazol-5-carboxylate ethyl is treated with a solution of hydrogen bromide in acetic acid, resulting in an overall yield of 86% of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate ethyl. Alternative processes have also been described for the preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate from ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1 / 7-pyrazol-5-carboxylate, such as a one-step bromination process using phosphorus oxybromide (POBrs) or phosphorus pentabromide (PBrs). However, POBrs and PBrs are not commercially available at the scale required for the production of anthranilamide-type compounds.Instead, PBrs is arguably the least expensive reagent to produce from an economic standpoint; however, it tends to agglomerate into a hard, solid block, making it difficult to store and transport. One way to overcome this problem is to prepare PBrs in situ by reacting them with bromine (Patent Application No. CN102399211 A). Both PBrs and bromine can be obtained from commercial suppliers on a sufficient scale. In this approach, PBrs are treated with bromine, producing a PBrs suspension, to which ethyl 1-(3-chloropyridine-2-1)-3-hydroxy-4,5-dihydro-1-pyrazol-5-carboxylate is added. However, one disadvantage of this method is that PBrs tends to coat the reactor walls as it forms, making the transfer of the mixture to another reactor complex. Γπηζηη / ζζηζ / Β / γίΛΐ This disclosure provides a useful novel process for preparing ethyl 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1-pyrazol-5-carboxylate and derivatives thereof in a convenient and cost-effective manner. COMPENDIUM A method for preparing a compound of Formula (I) rnnznn / ζζπζ / β / υιλι is provided herein. where R1 is halogen; each R2 is 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, Cs-Cs dialkylaminocarbonyl or Cs-Ce trialkylsilyl; R3es H or C1-C4 alkyl; X is N or CR4; R4 is H or R2; and n is 0, 1, 2 or 3, with the condition that, when X is CH, then n is at least 1, the method (1) comprising treating a compound of Formula (A) where X, R2 and n are as described above for Formula (I) and R3 is C1-C4 alkyl; with phosphorus tribromide (PBrs); and (2) treating the resulting product with bromine (Br2); and when preparing compounds of Formula (I) where R3 is H, (3) converting the compound formed in (2) into a compound where R3 is H. A method for preparing a compound of Formula (II) is also disclosed. R3O2C (II) pfrnznn / zznz / E / YiAi where R1 is halogen (and X, R2, R3 and n are as defined above for Formula (I)). The method is characterized by (4) treating a compound of Formula (A) according to the steps mentioned above to form a compound of Formula (I); and when using a compound of Formula (I) where R3 is C1-C4 alkyl to prepare a compound of Formula (II) where R3 is H, (5) converting the compound formed in (3) into a compound of Formula (II) where R3 is H. DETAILED DESCRIPTION In the preceding citations, the term “alkyl,” used alone or in compound words such as “alkylthio” or “haloalkyl,” includes linear or branched-chain alkyls, such as methyl, ethyl, n-propyl, i-propyl, or the various isomers of butyl, pentyl, or hexyl. “Alkenyl” may include linear or branched-chain alkenes such as 1-propenyl, 2-propenyl, and the various isomers of butenyl, pentenyl, and hexenyl. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes linear or branched-chain alkynes such as 1-propynyl, 2-propynyl, and the various isomers of butynyl, pentinyl, and hexynyl. “Alkynyl” may also include moieties comprising multiple triple bonds, such as 2,5-hexadiynyl. “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the various isomers of butoxy, pentoxy, and hexyloxy. “Alkoxyalkyl” indicates an alkoxy substitution on an alkyl group.Examples of “alkoxyalkyl” include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2, and CH3CH2OCH2CH2. “Alkylthio” includes linear or branched alkylthio groups, such as methylthio, ethylthio, and the various isomers of propylthio, butylthio, pentylthio, and hexylthio. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. “Cycloalkylalkyl” indicates an alkyl group substituted with a cycloalkyl group and includes, for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl, and cyclohexylmethyl. “Cycloalkylamino” means that the nitrogen atom of an amino group is bonded to a cycloalkyl radical and a hydrogen atom and includes groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, and cyclohexylamino.“(Alkyl)cycloalkylamino” means a cycloalkylamino group where the hydrogen atom is replaced by an alkyl radical; 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. In this application, the term “aryl” refers to an aromatic ring or ring system or a heteroaromatic ring or ring system, each ring or ring system being optionally substituted. The expression “aromatic ring system” indicates fully unsaturated carbocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic. “Aromatic” indicates that each of the ring atoms lies essentially in the same plane and has a p orbital perpendicular to the plane of the ring, and where (4n + 2) π electrons, where n is 0 or a positive integer, are associated with the ring to satisfy Hückel’s rule. The expression “aromatic carbocyclic ring system” includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic (e.g., phenyl and naphthyl).The expression “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 in which at least one ring atom is not carbon and may contain from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, provided that each heteroaromatic ring contains no more than 4 nitrogens, no more than 2 oxygens, and no more than 2 sulfurs (where aromatic indicates that Hückel's rule is satisfied). Heterocyclic ring systems can be joined through any available carbon or nitrogen by replacing a hydrogen atom on that carbon or nitrogen. More specifically, the term “aryl” refers to the remainder. pfrnznn / zznz / E / YiAi where R2y n are defined as before and the “3” indicates position 3 for substituents in the remainder. The term “halogen,” whether used alone or in compound words such as “haloalkyl,” includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in compound words such as “haloalkyl,” the alkyl group may be partially or fully substituted with halogen atoms, which may be the same or different. Examples of “haloalkyl” include F3C, ClCH2, CF3CH2, and CF3CCl2. The terms “haloalkenyl,” “haloalkynyl,” “haloalkoxy,” and similar terms are defined analogously to the term “haloalkyl.” Examples of “haloalkenyl” include (Cl)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of “haloalkynyl” include HC₂CCHOI, CFsC₂C, CCl₂C₂, and FCH2C=CCH2. Examples of “haloalkoxy” include CF3O, CCI3CH2O, HCF2CH2CH2O and CF3CH2O. Examples of “alkylcarbonyl” include C(O)CH3, C(O)CH2CH2CH3, and C(O)CH(CH3)2. Examples of “alkoxycarbonyl” include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O), and the various butoxy- or pentoxycarbonyl isomers. The terms “alkylaminocarbonyl” and “dialkylaminocarbonyl” include, for example, CH3NHC(=O), CH3CH2NHC(=O), and (CH3)2NC(=O). The total number of carbon atoms in a substituent group is indicated by the suffix C1-C1, where C1 and C1 are numbers from 1 to 8. For example, C1-C3 alkylsulfonyl designates from methylsulfonyl to propylsulfonyl. In the citations above, when a compound of Formula (I) contains a heteroaromatic ring, all substituents are attached to this ring through any available carbon or nitrogen atom, replacing a hydrogen atom on that carbon or nitrogen. When a group contains a substituent that can be hydrogen, for example, R4, then when this substituent is considered to be hydrogen, it is recognized that this is equivalent to the group not being substituted. Certain compounds of this invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. A person skilled in the art will appreciate that a stereoisomer may be more active and / or may exhibit beneficial effects when enriched with respect to another stereoisomer or stereoisomers, or when separated from the other stereoisomer or stereoisomers. Furthermore, the person skilled in the art knows how to selectively separate, enrich, and / or prepare such stereoisomers. Accordingly, the embodiments of this disclosure include: ρπηζηη / ζζηζ / Β / γίΛΐ Embodiment 1. A method for preparing a compound of Formula (1) where n is 1, 2, or 3. Embodiment 2. The method according to Embodiment 1 where n is 1. Embodiment 3. The method according to Embodiment 1 or 2 where R1 is Cl or Br. Embodiment 4. The method according to Embodiments 1 to 3 where R1 is Br. Embodiment 5. The method according to Embodiments 1 to 4 where each R2 is regardless of Cl or Br, and an R2 is in position 3. Realization 6. The method according to Realizations 1 to 5 where each R2 is Cl in position 3. Embodiment 7. The method according to Embodiments 1 to 6, wherein R3 is C1-C4 alkyl. Embodiment 8. The method according to Embodiments 1 to 7, wherein R3 is Et. Embodiment 9. The method according to Embodiments 1 to 8, wherein X is N. Embodiment 10. The method of Embodiments 1-10, wherein the method is carried out in presence of a solvent. Realization 11. The method of Realization 10 where the solvent is selected from acetonitrile, Λ / , / V-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobenzene, tetrachloromethane, dichlorobenzene, dichloromethane and 1,2-dichloroethane. Realization 12. The method of Realization 11 wherein the solvent is selected from acetonitrile, chlorobenzene, dichloromethane and 1,2-dichloroethane. Realization 13. The method of Realization 11 or 12 where the solvent is acetonitrile. Embodiment 14. The method of any of Embodiments 1-13, further comprising treating the product after step (2) with a base. Implementation 15. The method of any of Implementations 1-14, 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, β-methylimidazole, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, and potassium hydroxide. Implementation 16. The method of any of Implementations 14-15 wherein the base is selected from solid sodium bicarbonate, potassium carbonate and sodium carbonate. Implementation 17. The method of any of Implementations 14-16 where the base is solid sodium bicarbonate. Implementation 18. The method of Implementation 17 further comprising adding water after treating the product with solid sodium bicarbonate. Implementation 19. The method of any of Implementations 14-16 where the base is a saturated solution of sodium bicarbonate. Embodiment 20. The method of Embodiment 19 further comprising adding solid sodium bicarbonate after treating the product with the saturated sodium bicarbonate solution. Implementation 21. The method of any of Implementations 14-16 where the base is a sodium carbonate solution. Implementation 22. The method of any of Implementations 14-16 where the base is a potassium carbonate solution. Realization 23. Any method of Realizations 1-22, further comprising isolating a compound of Formula (I). Realization 24. The method of any of the Realizations 1-23 wherein the compound of Formula (I) is ethyl 3-bromo-1-(3-chloropyridin-2-11)-4,5-dihydro-1H-pyrazol-5-carboxylate. Implementation 25. A method for preparing a compound of Formula (II) where n is 1, 2 or 3. Realization 26. The method of Realization 25 where R1 is Cl or Br. Realization 27. The method of any of the Realizations 25-26 where R2 is independently Cl or Br. Realization 28. The method of Realization 27 where an R2 is in position 3. Realization 29. The method of any of Realizations 25-28 where R3 is C1-C4 alkyl. Realization 30. The method of any of the Realizations 25-29 where X is N. Realization 31. The method of any of the Realizations 25-30 further comprising isolating the compound of Formula (II). Realization 32. The method of any of the Realizations 25-30 wherein the compound of Formula (II) is ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1 / - / -pyrazol-5-carboxylate. Embodiment 33. The method of any of Embodiments 1-32, wherein steps (1) and (2) are carried out independently at a temperature of 15 °C to 50 °C. In one embodiment, useful temperatures at which steps (1) and (2) can be carried out include 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, and 50 °C. Realization 34. The method of any of Realizations 1-33 wherein the compound of Formula (I) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / - / -pyrazol-5-carboxylate, having the following structure: rnnznn / ζζπζ / β / υιλι r+nznn / zznz / B / YiAi and the compound of formula (A) is ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1 / - / -pyrazol-5-carboxylate, which has the structure: The following describes a step-by-step process for preparing compounds of Formula (I) and Formula (II). The processes for preparing a compound of Formula (A) are known in the art and have been described, for example, in document US 6 965 032 B2. The process for preparing a compound of Formula (I) and Formula (II) provided herein comprises (1) treating a compound of formula (A) where X, R2 and n are as defined above and R3 is H; or R3 is C1-C4 alkyl, with PBra in the presence of a solvent. The resulting product (2) is then treated with bromine to form a compound of Formula (I); (i) where X, R1, R2 and n are as defined above and R3 is H; or R3 is C1-C4 alkyl. Due to the excess of bromine, a quantity of a compound of Formula (I) is oxidized to form a compound of formula (II) Γπηζηη / ζζηζ / Β / γίΛΐ where X, R1, R2 and n are as defined above and R3 is H; or R3 is C1-C4 alkyl. Diagram 1 illustrates steps (1) and (2) in more detail. First, a compound of Formula (A)(1) is treated with PBrs in the presence of a solvent. Useful solvents include, but are not limited to, acetonitrile, A / ,A / -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 (2) is then treated with bromine, resulting in a suspension of a hydrobromide salt of a compound of Formula (I). Scheme 1 (A) (A') (l)-HBr 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, γ-methylimidazole, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, or potassium hydroxide. In one embodiment, the reaction mass is treated with solid sodium bicarbonate, followed by the addition of water to dissolve the solids. In another embodiment, the reaction mass is treated with a saturated sodium bicarbonate solution, followed by solid sodium bicarbonate to complete neutralization. In one embodiment, the reaction mass is neutralized by adding a sodium carbonate solution or a potassium carbonate solution. Optionally, the desired product, a compound of Formula (I), can be isolated using methods known to those skilled in the art, including, but not limited to, crystallization, extraction, and distillation. Using the process disclosed herein, a yield of approximately 90–95% of a compound of Formula (I) is obtained. It is worth noting that, in addition to a compound of Formula (I), the described process yields approximately 1% to 5% of a compound of Formula (II). It should also be noted that this process avoids the formation of PBrs. Without further details, it is believed that a person skilled in the art using the foregoing description can employ the present invention to its full extent. Therefore, the following Examples are to be interpreted as merely illustrative and not limiting disclosure in any way. The starting material for the following Examples may not necessarily have been prepared by a particular preparation process described in other Examples. Percentages are expressed by weight, except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume, unless otherwise indicated. It is also understood that any numerical range mentioned herein includes all values ​​from the lowest to the highest.For example, if a range is set as 10-50, it is intended that values ​​such as 12-30, 20-40, or 30-50, etc., be expressly listed in this specification. These are only examples of what is specifically intended, and it should be considered that all possible combinations of numerical values ​​between the lowest and highest listed values, inclusive, are expressly indicated in this application. The 1H NMR spectra are published in ppm relative to tetramethylsilane; “s” stands for singlet, “d” for doublet, “t” for triplet, “c” for quadruplet, “m” for multiplet, “dd” for doublet of doublets, “dt” for doublet of triplets, and “sa” for wide singlet. All reagents described in the following examples can be purchased from commercial suppliers. EXAMPLE 1 Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-5-carboxylate* and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylate** using solid sodium bicarbonate for neutralization 150 g of ethyl 1-(3-chloropyridin-2-11)-3-hydroxy-4,5-dihydro-1 / 7-pyrazol-5-carboxylate were treated with 90.3 g of phosphorus tribromide (PBr) in 750 mL of acetonitrile at 30-50°C for 0.5 h. The mixture was then treated with 53.3 g of bromine (Brz) at 30-40°C. The reaction mass was heated under reflux (at approximately 83°C; this can be carried out at a temperature of approximately 80°C to approximately 83°C) for 1-2 hours. Once the reaction was complete, the resulting suspension of ethyl HBr-3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate was treated in batches with 140 g of solid sodium bicarbonate. The mixture was then diluted by adding 600 g of water in batches. The pH of the two-phase mixture was adjusted to 7–8, and the phases were separated. The organic phase The solution was concentrated to remove acetonitrile under reduced pressure. The residue was mixed with 120 g of EtOH and 150 g of water. The resulting suspension was filtered to provide 173.7 g of ethyl 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1-pyrazol-5-carboxylate (98.1% w / w), corresponding to a yield of 92%. Due to the presence of an excess of bromine, some of the ethyl 3-bromo-1-(3-chloropyridin-2-1)-4,5-dihydro-1Hpyrazol-5-carboxylate was further oxidized, resulting in the generation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylate, corresponding to a yield of approximately 1.0% - 5.0%. It is worth noting that neutralizations with solid bicarbonate frequently do not go to completion due to the encapsulation of the sodium bicarbonate with the reaction products. Often, the addition of a phase-transfer catalyst is required. Surprisingly, in this case, the neutralization reaction proceeds to completion without a phase-transfer catalyst. Consequently, any process producing a suspension of ethyl HBr-3-bromo-1-(3-chloropyridin-2-11)-4,5-dihydro-1H-pyrazol-5-carboxylate can be expected to similarly benefit from the addition of solid bicarbonate as disclosed herein. EXAMPLE 2 Preparation of ethyl 3-bromo-1-(3-chloropyridine-2-1)-4,5-dihydro-1H-pyrazol-5-carboxylate* using PBrs prepared in situ In this example, PBrs were prepared in situ by reacting PBrs with bromine. Subsequently, ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1 / - / -pyrazol-5-carboxylate was added to the PBrs suspension. Specifically, 81 g of PBrs and 48 g of Brz were mixed in 1490 mL of acetonitrile at 20°C for 2 h. The resulting PBrs suspension was then treated with 68 g of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1 / - / -pyrazol-5-carboxylate, and the mixture was heated to 80°C for 2 h. After the reaction was complete, 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 provide 82.1 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5dihydro-1 H-pyrazol-5-carboxylate (90% w / w), which corresponds to a yield of 88%. EXAMPLE 3 Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-5-carboxylate* and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylate** using a sodium bicarbonate solution and solid sodium bicarbonate for neutralization 135 g of ethyl 1-(3-chloropyridine-2-11)-3-hydroxy-4,5-dihydro-1 / 7-pyrazol-5-carboxylate were treated with 74.4 g of phosphorus tribromide (PBrs) in 675 ml of acetonitrile at 30-50°C for 0.5 h. The mixture was then treated with 43.9 g of bromine (Brz) at 30-40°C. The reaction mass was heated under reflux (at approximately 83°C) for 1-2 hours. Once the reaction was complete, the resulting ethyl HBr-3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / - / -pyrazol-5-carboxylate suspension was treated in batches with 720 g of a sodium bicarbonate solution in water (50 g of solid sodium bicarbonate were dissolved in 675 g of water), followed by the addition of another 65 g of solid sodium bicarbonate in batches. The pH of the two-phase mixture was adjusted to 7–8, and the phases were separated. The organic phase was concentrated to remove acetonitrile under reduced pressure. The residue was mixed with 106 g of EtOH and 135 g of water. Γπηζηη / ζζηζ / Β / γίΛΐ The resulting suspension was filtered to provide 155 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1-Hpyrazol-5-carboxylate (98.0% w / w), corresponding to a yield of 91%. Due to the presence of excess bromine, some of the ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate was further oxidized, resulting in the generation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1 / - / -pyrazol-5-carboxylate, corresponding to a yield of approximately 1.0%–5.0%. EXAMPLE 4 Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-5-carboxylate* and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylate using a sodium carbonate solution and solid sodium carbonate for neutralization 135 g of ethyl 1-(3-chloropyridin-2-11)-3-hydroxy-4,5-dihydro-1 / - / -pyrazol-5-carboxylate were treated with 74.4 g of phosphorus tribromide (PBrs) in 675 ml of acetonitrile at 30-50°C for 0.5 h. The mixture was then treated with 43.9 g of bromine (B₂) at 30-40°C. The reaction mass was heated under reflux (at approximately 83°C) for 1-2 hours. Once the reaction was complete, the resulting suspension of ethyl HBr-3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1,5-pyrazol-5-carboxylate was treated in batches with 748 g of a sodium carbonate solution in water (73 g of solid sodium carbonate were dissolved in 675 g of water). The pH of the two-phase mixture was adjusted to 7–8, and the phases were separated. The organic phase was concentrated to remove acetonitrile under reduced pressure. The residue was mixed with 106 g of EtOH and 135 g of water.The resulting suspension was filtered to provide 152 g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / - / -pyrazol-5-carboxylate (98.5% w / w), corresponding to a yield of 90%. Due to the presence of excess bromine, some of the ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / - / -pyrazol-5-carboxylate was further oxidized, resulting in the generation of ethyl 3-bromo-1-(3-chloro-2-pyridin)-1 / 7-pyrazol-5-carboxylate, corresponding to a yield of approximately 1.0%–5.0%. EXAMPLE 5 Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-5-carboxylate* and ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylate using a potassium carbonate solution and solid potassium carbonate for neutralization 135 g of ethyl 1-(3-chloropyridine-2-1)-3-hydroxy-4,5-dihydro-1 / - / -pyrazol-5-carboxylate were treated with 74.4 g of phosphorus tribromide (PBra) in 675 mL of acetonitrile at 30-50°C for 0.5 h. The mixture was then treated with 43.9 g of bromine (Br2) at 30-40°C. The reaction mass was heated under reflux (at approximately 83°C) for 1-2 hours. Once the reaction was complete, the resulting ethyl HBr-3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1 / - / -pyrazol-5-carboxylate suspension was treated in batches with 768 g of a potassium carbonate solution in water (93 g of solid potassium carbonate were dissolved in 675 g of water). The pH of the two-phase mixture was adjusted to 7–8, and the phases were separated. The organic phase was concentrated to remove acetonitrile under reduced pressure. The residue was mixed with 106 g of EtOH and 135 g of water.The resulting suspension was filtered to provide 155 g of ethyl 3-bromo-1-(3chloropyridin-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate (98.3% w / w), corresponding to a yield of 92%. Due to the presence of excess bromine, some of the ethyl 3-bromo-1-(3-chloropyridin2-yl)-4,5-dihydro-1H-pyrazol-5-carboxylate was further oxidized, resulting in the generation of ethyl 3-bromo-1-(3-chloro-2-pindinyl)-1 / 7-pyrazol-5-carboxylate, corresponding to a yield of approximately 1.0% - 5.0% *1H NMR (DMSO-d6, 400 MHz) δ = 1.12 (t, J= 7.0 Hz, 3H), 3.24-3.31 (m, 1H), 3.54-3.61 (m, 1H), 4.08 (c, J= 7.0 Hz, 2H), 5.14-5.19 (m, 1H), 6.98 (dd, J= 4.8 Hz, J= 7.6 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 8.10 (d, J= 4.4 Hz, 1H). **1H NMR ((DMSO-d6, 400 MHz) δ = 1.20 (t, J = 7.2 Hz, 3H), 4.23 (c, J= 7.2 Hz, 2H), 6.94 (s, 1H), 7.44 (dd, J-4.8 Hz, J = 8.1 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 8.51 (d, J-4.8 Hz, 1H). Using the procedures described herein, together with methods known in the art, the following compounds in Tables 1 to 3 can be prepared. The following abbreviations are used in the Tables: tes is tertiary, s is secondary, n is normal, i is iso, Me is methyl, Et is ethyl, Pr is propyl, iPr is isopropyl and t-Bu is tertiary butyl. TABLE 1 pfrnznn / zznz / E / YiAi R1es Cl R2 XesN XesCH R2 X es CCI X es CBr R3 R2 R3 R2 R3 R2 R3 R3 R2 R3 R2 R3 R2 R3 Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl f-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl f-Bu Br t-Bu R1es Br XesN R2 XesCH R3 X es CCI X es CBr R2 R3 R2 R3 R3 R2 R2 R3 R2 R3 R2 R3 R2 R3 Cl H Br H Cl H Br H Cl H Br H Cl H Br H R1es Br XesN XesCH R2 X es CCI X es CBr R2 R3 R2 R3 R2 R3 R2 R3 R3 R2 R3 R2 R3 R2 R3 Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu rnnznn / ζζηζ / Β / γίΛΐ TABLA 2 R1 R1es Cl XesN R2 XesCH R3 X es CCI X es CBr R2 R3 R2 R3 R3 R2 R2 R3 R2 R3 R2 R3 R2 R3 Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu R1es Br XesN XesCH X es CCI X es CBr R2 R3 R2 R3 R2 R3 R2 R3 R2 R3 R2 R3 R2 R3 R2 R3 Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et R1es Br XesN XesCH R2 / -Pr Cl / -Pr Br / -Pr Cl / -Pr Br / -Pr Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl / -Bu Br / -Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Γπηζηη / ζζηζ / Β / γίΛΐ Utility Compounds of Formulas (I), (II) and (A) are useful as synthetic intermediates to prepare a compound of Formula (III) where X, R1, R2y are not defined as before; R6es CH3, Cl or Br; R7es CN, F, Cl, Br, I or CFs; y R8es are C1-C4 alkyl. Compounds of Formula (III) are useful as insecticides. Compounds of Formula (III) can be prepared from compounds of formula (II) and in turn from compounds of Formula (A) and (I) by the processes previously disclosed in document US 6 965 032 B2.

Claims

1. A method for preparing a compound of Formula (I) rnnznn / ζζπζ / β / υιλι where R1 is a halogen; each R2 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Cs-Ce cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, Cs-Ce 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; R3 is H or C1-C4 alkyl; X is N or CR4; R4 is H or R2; and n is 0, 1, 2 or 3, with the condition that when X is CH then n is at least 1, the method comprising: (a) treating a compound of Formula (A) where R3 is C1-C4 alkyl; with a phosphorus tribromide; (b) treating the product resulting from step (a) with bromine;and when preparing compounds of Formula (I) where R3 is H, convert the compound formed in (a) into a compound where R3 is H.; 2. The method of claim 1 where n is 1, 2 or 3.

3. The method of claim 1 or 2 where R1 is Cl or Br.

4. The method of claims 1-3 wherein R2 is independently Cl or Br.

5. The method of claim 4 wherein an R2 is in position 3.

6. The method of any of claims 1-5 wherein R3 is C1-C4 alkyl.

7. The method of any of claims 1-6 where X is N.

8. The method of any of claims 1-7 wherein the compound of Formula (I) is ethyl 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 / 7-pyrazol-5-carboxylate, having the following structure: Γπηζηη / ζζηζ / Β / γίΛΐ and the compound of formula (A) ethyl carboxylate, having the structure: 1-(3-chloropyridine-2-yl)-3-hydroxy-4,5-dihydro-1 / 7-pyrazol-5- 9. The method of any of claims 1-8 wherein steps (a) and (b) are carried out independently at a temperature of 15 °C to 50 °C.

10. The method of any of claims 1-9 wherein the method is carried out in the presence of a solvent.

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 of claim 10 or 11 wherein the solvent is selected from acetonitrile, chlorobenzene, dichloromethane and 1,2-dichloroethane.

13. The method of any of claims 10-12 wherein the solvent is acetonitrile.

14. The method of any of claims 1-13, further comprising: (c) treating the product resulting from step (b) with a base.

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, / V-methylimidazole, potassium hydrogen phosphate, sodium hydrogen phosphate, hydroxide sodium and potassium hydroxide.

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 method of any of claims 14-16 wherein the base is solid sodium bicarbonate.

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

19. The method of any of claims 14-16 wherein the base is a saturated solution of sodium bicarbonate.

20. The method of claim 19 further comprising adding solid sodium bicarbonate after treating the product resulting from step (b) with the saturated sodium bicarbonate solution.

21. The method of any of claims 14-16 wherein the base is a sodium carbonate solution.

22. The method of any of claims 14-16 wherein the base is a potassium carbonate solution.

23. Any method of claims 1-22, which optionally further comprises isolating a compound of Formula (I).

24. A method according to any of claims 1-22 for preparing a compound of Formula (II) pfrnznn / zznz / E / YiAi where R1 is a halogen; each R2 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, Cs-Ce 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, Cs-Ce (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, or C3-C6 trialkylsilyl; R3 is H or C1-C4 alkyl; X is N or CR4; R4 is H or R2; yn is 0, 1, 2 or 3, with the condition that when X is CH then n is at least 1.

25. The method of claim 24 where n is 1, 2 or 3.

26. The method of claim 24 or 25 where R1 is Cl or Br.

27. The method of any of claims 24-26 wherein R2 is independently Cl or Br.

28. The method of claim 27 wherein an R2 is in position 3.

29. The method of any of claims 24-28 wherein R3 is C1-C4 alkyl.

30. The method of any of claims 24-29 where X is N.

31. The method of any of claims 24-30 wherein the compound of Formula (II) is ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1 / 7-pyrazol-5-carboxylate, having the following structure: r+nznn / ζζπζ / β / υιλι cr 32. The method of any of claims 24-31, further comprising isolating the compound of Formula (II).