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

Abstract

A method for preparing compounds of formula (I) and (II) is disclosed, wherein R 1 , R 2 , R 3 , X and n are as defined in this disclosure.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 888,667, filed on August 19, 2019, and U.S. Provisional Application No. 62 / 890,154, filed on August 22, 2019, the disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0003] 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 process disclosed herein can be used to prepare certain anthranilamide compounds of interest as insecticides. Background Art

[0004] 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. U.S. Pat. No. 6,965,032 to DuPont has described the preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate in a two-step process from ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate. In the first step, ethyl l-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-lH-pyrazole-5-carboxylate was treated with benzenesulfonyl chloride to give ethyl l-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-lH-pyrazole-5-carboxylate. In the second step, ethyl l-(3-chloropyridin-2-yl)-3-((phenylsulfonyl)oxy)-4,5-dihydro-lH-pyrazole-5-carboxylate was treated with a solution of hydrogen bromide in acetic acid to give ethyl 3-bromo-l-(3-chloropyridin-2-yl)-4,5-dihydro-lH-pyrazole-5-carboxylate in 86% overall yield. Alternative methods for preparing 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate from 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate have also been described, such as the one-step bromination method using phosphorus oxybromide (POBr3) or phosphorus pentabromide (PBr5). However, POBr3 and PBr5 have not yet reached the commercial scale required for producing o-aminobenzamide compounds. Although the production cost of PBr5 may be the lowest, it tends to agglomerate into hard solid blocks, making transportation and storage difficult. One way to avoid this problem is to prepare PBr5 (patent application number CN 102399211 A) in situ by reacting PBr3 and bromine. PBr3 and bromine can be commercially available on a sufficient scale. In this option, PBr3 is treated with bromine to give 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 drawback of this approach is that PBr5 tends to coat the walls of the reactor as it forms, which makes transferring the mixture to another reactor challenging.

[0005] The present disclosure provides a novel process 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. Summary of the invention

[0006] Provided herein is a method for preparing a compound having formula (I)

[0007]

[0008] Where R 1 It is a halogen;

[0009] Each R 2 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, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl;

[0010] R 3 is H or C1-C4 alkyl;

[0011] X is N or CR4;

[0012] R 4 Is H or R 2 ;and

[0013] n is 0, 1, 2 or 3, provided that when X is CH, then n is at least 1, the method comprising (1): treating a compound having the formula (A) with phosphorus tribromide (PBr3)

[0014]

[0015] Among them, X, R 2 and n are as described above for formula (I) and R 3 is a C1-C4 alkyl group;

[0016] and (2) treating the resulting product with bromine (Br2); and when preparing a compound wherein R 3 When the compound of formula (I) is H, (3) converting the compound formed in (2) into a compound wherein R 3 It is a compound of H.

[0017] Also disclosed is a method for preparing a compound having formula (II),

[0018]

[0019] Where R 1 is a halogen (and X, R 2 , R 3and n is as defined above for formula (I)). The method is characterized in that: (4) treating a compound of formula (A) according to the steps described above for forming a compound of formula (I); and when using a compound wherein R 3 is a C1-C4 alkyl compound having the formula (I) wherein R 3 When the compound of formula (II) is H, (5) converting the compound formed in (3) into a compound wherein R 3 is a compound having formula (II) wherein: DETAILED DESCRIPTION

[0020] In the above detailed description, the term "alkyl", used alone or in compound words such as "alkylthio" or "haloalkyl", includes straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, or different butyl, pentyl, or hexyl isomers. "Alkenyl" can include straight or branched olefins, such as 1-propenyl, 2-propenyl, and different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes, such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight or branched alkynes, such as 1-propynyl, 2-propynyl, and different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include a portion consisting of multiple triple bonds, such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy and different butoxy, pentoxy and hexoxy isomers. "Alkoxyalkyl" means that the alkoxy on the alkyl group replaces. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2."Alkylthio" includes branched or straight chain alkylthio moieties, such as methylthio, ethylthio and different propylthio, butylthio, pentylthio and hexylthio isomers. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Cycloalkylalkyl" indicates an alkyl substituted by a cycloalkyl and includes, for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl and cyclohexylmethyl. "Cycloalkylamino" means that the amino nitrogen atom is attached 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 the 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 group in the (alkyl)cycloalkylamino group is a C1-C4 alkyl group, while the cycloalkyl group in the cycloalkylamino group and the (alkyl)cycloalkylamino group is a C3-C6 cycloalkyl group.

[0021] In the present application, the term "aryl" refers to an aromatic ring or ring system or a heteroaromatic ring or ring system, each of which is optionally substituted. The term "aromatic ring system" refers to fully unsaturated carbocyclic and heterocyclic rings in which at least one ring in a polycyclic system is aromatic. Aromatic indicates that each ring atom is substantially in the same plane and has a p-orbital perpendicular to the plane of the ring, and that (4n+2) π electrons (where n is 0 or a positive integer) are associated with the ring to comply with Huckel's rule. The term "aromatic carbocyclic ring system" includes fully aromatic carbocyclic rings and carbocyclic rings in which at least one ring in a polycyclic 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 in a polycyclic 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 Huckel's rule is satisfied). The heterocyclic ring system may be attached via any available carbon or nitrogen by replacing a hydrogen on said carbon or nitrogen. More specifically, the term "aryl" refers to the following moieties:

[0022]

[0023] Where R 2 and n are as defined above and "3" indicates that the substituent is at the 3 position of the moiety.

[0024] The term "halogen", alone or in a compound word such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. In addition, when used in a compound word such as "haloalkyl", the alkyl group may be partially substituted or completely substituted by halogen atoms which may be the same or different. Examples of "haloalkyl" include F3C, ClCH2, CF3CH2 and CF3CCl2. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy" and the like are similar to the definition of 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.

[0025] 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 different butoxycarbonyl or pentyloxycarbonyl isomers. The terms "alkylaminocarbonyl" and "dialkylaminocarbonyl" include, for example, CH3NHC(=O), CH3CH2NHC(=O), and (CH3)2NC(=O).

[0026] The total number of carbon atoms in a substituent is represented by "C i -C j " prefix represents, wherein i and j are numbers from 1 to 8. For example, C1-C3 alkylsulfonyl represents methylsulfonyl to propylsulfonyl. In the above description, when the compound having formula (I) contains a heteroaromatic ring, all substituents are attached to the ring through any available carbon or nitrogen by replacing a hydrogen on said carbon or nitrogen.

[0027] When a group contains a substituent which may be hydrogen, for example R 4 When the substituent is regarded as hydrogen, this is considered to be equivalent to the group being unsubstituted.

[0028] Certain compounds of the present invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Those skilled in the art will appreciate that a stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to one or more other stereoisomers, or when separated from one or more other stereoisomers. In addition, those skilled in the art know how to separate, enrich, and / or selectively prepare the stereoisomers. Thus, embodiments of the present disclosure include:

[0029] Example 1. A method for preparing a compound of formula (I) wherein n is 1, 2 or 3.

[0030] Embodiment 2. The method according to embodiment 1, wherein n is 1.

[0031] Embodiment 3. The method according to embodiment 1 or 2, wherein R 1 It is Cl or Br.

[0032] Embodiment 4. The method according to embodiments 1 to 3, wherein R 1 It's Br.

[0033] Embodiment 5. The method according to embodiments 1 to 4, wherein each R 2 are independently Cl or Br, and one R 2In 3rd place.

[0034] Embodiment 6. The method according to embodiments 1 to 5, wherein:

[0035] Each R 2 It is Cl at the 3 position.

[0036] Embodiment 7. The method according to embodiments 1 to 6, wherein R 3 It is a C1-C4 alkyl group.

[0037] Embodiment 8. The method according to embodiments 1 to 7, wherein R 3 It's Et.

[0038] Embodiment 9. The method according to embodiments 1 to 8, wherein X is N.

[0039] Embodiment 10. The method according to embodiments 1-10, wherein the method is carried out in the presence of a solvent.

[0040] Embodiment 11. The method according to embodiment 10, wherein the solvent is selected from acetonitrile, N,N-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobenzene, carbon tetrachloride, dichlorobenzene, dichloromethane, and 1,2-dichloroethane.

[0041] Embodiment 12. The method according to embodiment 11, wherein the solvent is selected from acetonitrile, chlorobenzene, dichloromethane, and 1,2-dichloroethane.

[0042] Embodiment 13. The method according to embodiment 11 or 12, wherein the solvent is acetonitrile.

[0043] Embodiment 14. The method according to any one of embodiments 1-13, further comprising treating the product after step (2) with a base.

[0044] Embodiment 15. A method according to any one of embodiments 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, N-methylimidazole, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, and potassium hydroxide.

[0045] Embodiment 16. The method according to any one of embodiments 14-15, wherein the base is selected from solid sodium bicarbonate, potassium carbonate, and sodium carbonate.

[0046] Embodiment 17. The method according to any one of embodiments 14-16, wherein the base is solid sodium bicarbonate.

[0047] Embodiment 18. The method of embodiment 17, further comprising adding water after treating the product with solid sodium bicarbonate.

[0048] Embodiment 19. The method according to any one of embodiments 14-16, wherein the base is a saturated sodium bicarbonate solution.

[0049] Embodiment 20. The method of embodiment 19, further comprising adding solid sodium bicarbonate after treating the product with saturated sodium bicarbonate solution.

[0050] Embodiment 21. The method according to any one of embodiments 14-16, wherein the base is sodium carbonate solution.

[0051] Embodiment 22. The method according to any one of embodiments 14-16, wherein the base is potassium carbonate solution.

[0052] Embodiment 23. The method of any one of embodiments 1-22, further comprising isolating the compound having formula (I).

[0053] Embodiment 24. The method according to any one of embodiments 1-23, wherein the compound of formula (I) is 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester.

[0054] Example 25. A method for preparing a compound having formula (II)

[0055] Where n is 1, 2 or 3.

[0056] Embodiment 26. The method according to embodiment 25, wherein R 1 It is Cl or Br.

[0057] Embodiment 27. The method according to any one of embodiments 25-26, wherein R 2 is independently Cl or Br.

[0058] Embodiment 28. The method according to embodiment 27, wherein one R 2 It is in the 3rd position.

[0059] Embodiment 29. The method according to any one of embodiments 25-28, wherein R 3 It is a C1-C4 alkyl group.

[0060] Embodiment 30. The method of any one of embodiments 25-29, wherein X is N.

[0061] Embodiment 31. The method according to any one of embodiments 25-30, further comprising isolating the compound of formula (II).

[0062] Embodiment 32. The method according to any one of embodiments 25-30, wherein the compound of formula (II) is 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester.

[0063] Embodiment 33. The method according to any one of embodiments 1-32, wherein steps (1) and (2) are independently performed at a temperature of from 15° C. to 50° C. In one embodiment, useful temperatures at which steps (1) and (2) can be performed include 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., and 50° C.

[0064] Embodiment 34. The method according to any one of embodiments 1-33, wherein the compound of formula (I) is 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester having the following structure:

[0065]

[0066] And the compound of formula (A) is ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate having the following structure:

[0067]

[0068] The following describes a stepwise method for preparing compounds of formula (I) and formula (II).

[0069] Processes for preparing compounds of formula (A) are known in the art and have been described, for example, in US 6,965,032 B2.

[0070] The method provided herein for preparing compounds of formula (I) and formula (II) comprises: (1) treating a compound of formula (A) with PBr3 in the presence of a solvent

[0071]

[0072] Among them, X, R 2 and n are as defined above and R 3 is H; or R 3 is a C1-C4 alkyl group. (2) the resulting product is then treated with bromine to form a compound having formula (I);

[0073]

[0074] Among them, X, R 1 , R 2and n are as defined above and R 3 is H; or R 3 It is a C1-C4 alkyl group.

[0075] Due to the excess of bromine, a certain amount of the compound having formula (I) is oxidized to form a compound having formula (II)

[0076]

[0077] Among them, X, R 1 , R 2 and n are as defined above and R 3 is H; or R3 is C1-C4 alkyl.

[0078] Scheme 1 illustrates steps (1) and (2) in more detail.

[0079] (1) First, a compound of formula (A) is 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, carbon tetrachloride, 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. (2) The resulting product is then treated with bromine to obtain a slurry of the hydrobromide salt of the compound of formula (I).

[0080] Solution 1

[0081]

[0082]

[0083] 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 hydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, or potassium hydroxide. In one embodiment, the reaction mass is treated with solid sodium bicarbonate, and water is subsequently added to dissolve the solids. In one embodiment, the reaction mass is treated with a saturated sodium bicarbonate solution, and then treated with solid sodium bicarbonate to complete neutralization.

[0084] In one embodiment, the reaction mass is neutralized by adding sodium carbonate solution or potassium carbonate solution.

[0085] Optionally, the desired product (compound of formula (I)) can be separated by methods known to those skilled in the art, including but not limited to crystallization, extraction and distillation. The method disclosed herein achieves a yield of about 90%-95% of the compound of formula (I). It is noteworthy that, in addition to the compound of formula (I), the method produces about 1% to 5% of the compound of formula (II). It should be noted that the method avoids the formation of PBr5.

[0086] Without further elaboration, it is believed that those skilled in the art can make the most of the present invention using the previous description. Therefore, the following examples should be interpreted as being illustrative only and not limiting the present disclosure in any way. The starting materials of the following examples may not necessarily be prepared by a specific preparation run, and its procedures are described in other embodiments. Percentages are by weight, except for chromatographic solvent mixtures or otherwise specified. Unless otherwise specified, the number and percentage of chromatographic solvent mixtures are by volume. It should also be understood that any numerical ranges listed herein include all values ​​from the lower limit to the upper limit. For example, if the range is specified as 10-50, it is expected that values ​​such as 12-30, 20-40 or 30-50 are explicitly listed in this specification. These are only examples of special expectations, and all possible combinations of numerical values ​​between the lowest and highest values ​​listed (and including the lowest and highest values) will be considered to be clearly stated in this application.

[0087] 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 two doublets, "dt" means two triplets, and "br s" means broad singlet. All reagents described in the following examples are available from commercial sources.

[0088] Example 1

[0089] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyridin-2-yl using solid sodium bicarbonate for neutralization Ethyl oxadiazole-5-carboxylate * and 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester **

[0090] 150g 1-(3-chloropyridine-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-ethyl formate is treated with 90.3g phosphorus tribromide (PBr3) in 750ml acetonitrile at 30°C-50°C for 0.5 hour. Then the mixture is treated with 53.3g bromine (Br2) at 30°C-40°C. The reaction mass is heated to reflux (about 83°C, which can be carried out at about 80°C to about 83°C) for 1-2 hours. After the reaction is complete, the obtained 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl formate-HBr slurry is treated in batches with 140g solid sodium bicarbonate. Then the mixture is diluted by adding 600g water in batches. The mixture of the two phases is adjusted to pH 7-8 and each phase is separated. The organic phase is concentrated to remove acetonitrile under reduced pressure. The residue was mixed with 120 g of EtOH and 150 g of water. The resulting slurry was filtered to obtain 173.7 g of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester (98.1 wt.%), corresponding to a yield of 92%. Due to the presence of excess bromine, part of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester was further oxidized, resulting in the production of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester, corresponding to a yield of about 1.0%-5.0%.

[0091] It should be noted that neutralization with solid sodium bicarbonate often cannot be completed due to encapsulation of the reaction product by sodium bicarbonate. It is usually necessary to add a phase transfer catalyst. Surprisingly, in this case, the neutralization reaction is carried out completely without a phase transfer catalyst. Therefore, it is expected that any method for producing 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester-HBr slurry will similarly benefit from the addition of solid bicarbonate as disclosed herein.

[0092] Example 2

[0093] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid using in situ prepared PBr5 Ethyl ester *

[0094] In this example, PBr5 was prepared in situ by reacting PBr3 with bromine. 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester was then added to the PBr5 slurry.

[0095] Specifically, 81g PBr3 and 48g Br2 were mixed in 1490mL acetonitrile at 20°C for 2 hours. The resulting PBr5 slurry was then treated with 68g 1-(3-chloropyridine-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-ethyl formate and the mixture was heated to 80°C for 2 hours. 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 obtain 82.1g 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl formate (90wt%), corresponding to a yield of 88%.

[0096] Example 3

[0097] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-4-nitropropene using sodium bicarbonate solution and solid sodium bicarbonate for neutralization 5-Dihydro-1H-pyrazole-5-carboxylic acid ethyl ester * and 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester**

[0098] 135g 1-(3-chloropyridine-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate was treated with 74.4g phosphorus tribromide (PBr3) in 675ml acetonitrile at 30°C-50°C for 0.5 hour. Then the mixture was treated with 43.9g bromine (Br2) at 30°C-40°C. The reaction mass was heated to reflux (about 83°C) for 1-2 hours. After the reaction was completed, the resulting 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate-HBr slurry was treated with 720g sodium bicarbonate solution in water (50g solid sodium bicarbonate was dissolved in 675g water) in batches, and then another 65g solid sodium bicarbonate was added in batches. The mixture of the two phases was adjusted to pH 7-8 and each phase was separated. The organic phase is concentrated to remove acetonitrile under reduced pressure. Residue is mixed with 106g EtOH and 135g water. Filter the resulting slurries to obtain 155g 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl formate (98.0wt.%), corresponding to 91% productive rate. Due to the presence of excessive bromine, part of 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl formate is further oxidized, resulting in the production of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-ethyl formate, corresponding to a productive rate of about 1.0%-5.0%.

[0099] Example 4

[0100] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydropyridin-1-yl using sodium carbonate solution and solid sodium carbonate for neutralization Ethyl hydrogen-1H-pyrazole-5-carboxylate * and 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester **

[0101] 135g 1-(3-chloropyridine-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate was treated with 74.4g phosphorus tribromide (PBr3) in 675ml acetonitrile at 30°C-50°C for 0.5 hour. Then the mixture was treated with 43.9g bromine (Br2) at 30°C-40°C. The reaction mass was heated to reflux (about 83°C) for 1-2 hours. After the reaction was completed, the resulting 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate-HBr slurry was treated with 748g sodium carbonate solution in water (73g solid sodium carbonate was dissolved in 675g water) in batches. The mixture of the two phases was adjusted to pH 7-8 and each phase was separated. The organic phase was concentrated to remove acetonitrile under reduced pressure. The residue was mixed with 106 g EtOH and 135 g water. The resulting slurry was filtered to obtain 152 g 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate (98.5 wt.%), corresponding to a 90% yield. Due to the presence of excess bromine, part of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate was further oxidized, resulting in the production of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-ethyl carboxylate, corresponding to a yield of about 1.0%-5.0%.

[0102] Example 5

[0103] Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydropyridin-1-yl using potassium carbonate solution and solid potassium carbonate for neutralization Ethyl hydrogen-1H-pyrazole-5-carboxylate * and 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester **

[0104] 135g 1-(3-chloropyridine-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate was treated with 74.4g phosphorus tribromide (PBr3) in 675ml acetonitrile at 30°C-50°C for 0.5 hour. Then the mixture was treated with 43.9g bromine (Br2) at 30°C-40°C. The reaction mass was heated to reflux (about 83°C) for 1-2 hours. After the reaction was completed, the resulting 3-bromo-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate-HBr slurry was treated with 768g potassium carbonate solution in water (93g solid potassium carbonate was dissolved in 675g water) in batches. The mixture of the two phases was adjusted to pH 7-8 and each phase was 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 slurry was filtered to obtain 155 g of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate (98.3 wt.%), corresponding to a yield of 92%. Due to the presence of excess bromine, part of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-ethyl carboxylate was further oxidized, resulting in the production of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-ethyl carboxylate, corresponding to a yield of about 1.0%-5.0%.

[0105] *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).

[0106] **1 H NMR (DMSO-d6, 400MHz) δ = 1.20 (t, J = 7.2Hz, 3H), 4.23 (q, J = 7.2Hz, 2H), 6.94 (s, 1H ), 7.44 (dd, J = 4.8Hz, J = 8.1Hz, 1H), 7.91 (d, J = 8.1Hz, 1H), 8.51 (d, J = 4.8Hz, 1H).

[0107] The following compounds in Tables 1 to 3 can be prepared by the procedures described herein together with methods known in the art. The following abbreviations are used in the tables: t is tert-, 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 tert-butyl.

[0108] Table 1

[0109]

[0110] R 1 It is Cl

[0111]

[0112] R 1 It's Br

[0113]

[0114] Table 2

[0115]

[0116] R 1 It is Cl

[0117]

[0118] R 1 It's Br

[0119]

[0120] Table 3

[0121]

[0122]

[0123] utility

[0124] Compounds of formula (I), (II) and (A) are used as synthetic intermediates for preparing compounds of formula (III)

[0125]

[0126] Among them, X, R 1 , R 2 and n are as defined above; R 6 is CH3, Cl or Br; R 7 is CN, F, Cl, Br, I or CF3; and R 8 It is a C1-C4 alkyl group.

[0127] The compounds of formula (III) are useful as insecticides.

[0128] Compounds of formula (III) can be prepared from compounds of formula (II), and in turn from compounds of formula (A) and (I), by the method previously disclosed in US 6,965,032 B2.

Claims

1. A method for preparing a compound having formula (I) Where R 1 It is bromine; Each R 2 are independently halogen; R 3 is a C1-C4 alkyl group; X is N; and n is 1, The method includes: (a) treating a compound of formula (A) with phosphorus tribromide Where R 3 is a C1-C4 alkyl group; (b) treating the product obtained from step (a) with bromine; The method is carried out in the presence of a solvent selected from acetonitrile, N,N-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobenzene, carbon tetrachloride, dichlorobenzene, dichloromethane, and 1,2-dichloroethane.

2. The method of claim 1, wherein R 2 is independently Cl or Br.

3. The method of claim 2, wherein R 2 In 3rd place.

4. The method of claim 1, wherein R 3 It is ethyl.

5. The method of claim 1, wherein the compound of formula (I) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate having the following structure: And the compound of formula (A) is ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate having the following structure:

6. The method of claim 1, wherein steps (a) and (b) are independently performed at a temperature of from 15°C to 50°C.

7. The method of claim 1, wherein the solvent is selected from acetonitrile, chlorobenzene, dichloromethane, and 1,2-dichloroethane.

8. The method of claim 7, wherein the solvent is acetonitrile.

9. The method according to any one of claims 1 to 8, further comprising: (c) treating the product obtained in step (b) with a base.

10. The method of claim 9, wherein the base is selected from solid sodium bicarbonate, saturated 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.

11. The method of claim 9, wherein the base is selected from solid sodium bicarbonate, saturated sodium bicarbonate, sodium carbonate, and potassium carbonate.

12. The process of claim 9, wherein the base is solid sodium bicarbonate.

13. The method of claim 12, further comprising adding water after treating the product obtained from step (b) with the solid sodium bicarbonate.

Images