3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate and its synthesis method and application

Abstract

The invention discloses 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate and a synthesis method and application thereof. According to the invention, 3-mercaptopropionate and 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole are reacted in the presence of a catalyst to prepare 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. The method simplifies the synthesis process, has the advantages of fast reaction speed, low impurity content, high product yield, mild reaction conditions, low equipment cost, extensive synthesis process and post-treatment process, and the 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate can be used as a sulfonepyraclostrobin intermediate, thereby avoiding many shortcomings of a 5,5-dimethyl-4,5-dihydroisoxazolethioamidine hydrochloride intermediate.

Description

Technical Field

[0001] The invention relates to 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate, and also relates to a synthesis method of the 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate and application of the 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate as a sulfonepyraclostrobin intermediate, belonging to the technical field of sulfonepyraclostrobin preparation. Background Art

[0002] Pyroxasulfone is an isoxazole herbicide developed by Kumizu Chemical Co., Ltd. Its chemical name is 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, and its molecular formula is C 12 H 14 F5N3O4S, molecular weight is 391.32, CAS registration number is 447399-55-5. Sulfonepyraclostrobin has the characteristics of broad herbicidal spectrum, high activity, low dosage and good safety, so it has received widespread attention. Sulfonepyraclostrobin can be used as a pre-emergence soil treatment agent in most crop fields. Because it belongs to the class of very long chain fatty acid elongation synthase inhibitor herbicides, it exerts its efficacy by inhibiting very long chain fatty acid elongation synthase (VLCFAE). It can inhibit the conversion of stearic acid to arachidic acid, arachidic acid to behenic acid, behenic acid to tetradecanoic acid, tetradecanoic acid to cerotic acid, and cerotic acid to montanic acid in the biosynthetic pathway of very long chain fatty acid synthase in plants, and finally inhibit the synthesis of myristic acid to exert its effect. Its structure is as follows:

[0003]

[0004] At present, there are few reports on the synthesis process of sulfonepyraclostrobin. Patent CN102666502 discloses the following process route: under alkaline conditions, 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, formaldehyde aqueous solution and 5,5-dimethyl-4,5-dihydroisoxazolethiocarbamide hydrochloride are subjected to condensation reaction in water to obtain intermediate A, intermediate A is then alkylated with difluorochloromethane to obtain intermediate B, intermediate B is oxidized with hydrogen peroxide to obtain sulfonepyraclostrobin; the reaction formula is as follows:

[0005]

[0006] The above process route uses 5,5-dimethyl-4,5-dihydroisoxazolesulfonamidine hydrochloride as an intermediate. During the reaction of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, formaldehyde aqueous solution and 5,5-dimethyl-4,5-dihydroisoxazolesulfonamidine hydrochloride, a large amount of ammonia nitrogen wastewater will be produced, which will damage the ecological environment, cause eutrophication of water bodies and loss of balance of water bodies, and even have toxic effects on people and organisms.

[0007] Patent CN115335375A discloses a method for synthesizing a sulfonepyraclostrobin intermediate, wherein an isoxazole of formula (II) is reacted with a sulfiding agent to produce an S-substituted thioisoxazole of formula (III); finally, the thioisoxazole is combined with a pyrazole of formula (IV) to obtain a sulfonepyraclostrobin intermediate of formula (I); the reaction route is as follows:

[0008]

[0009] The sulfiding reagent used in the synthesis of S-substituted thioisoxazole of formula (III) in the above route is dimethylthioformamide, thiosulfate, dithiooxamide, alkyl xanthate, thiobenzamide, N-substituted thiourea and thioacetate, etc., which are expensive and need to be completed under nitrogen protection. The reaction operation is complicated, the synthesized thioisoxazole is not easy to preserve, and the industrial practical value is low. Summary of the invention

[0010] In view of the shortcomings of sulfonepyraclostrobin intermediates in the existing process, the present invention provides a 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate, which can replace 5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate as an intermediate of sulfonepyraclostrobin, and does not generate ammonia nitrogen wastewater that is difficult to treat during the preparation of sulfonepyraclostrobin. The preparation method of the compound is simple and has strong operability, and has good industrial practical value.

[0011] The 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate of the present invention has the structural formula (III) as follows:

[0012]

[0013] In the formula (III), R is methyl, ethyl, propyl, butyl, isobutyl or cyclohexyl.

[0014] The present invention also provides a method for synthesizing the above-mentioned 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. The 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate is obtained by reacting 3-mercaptopropionic acid ester represented by formula (I) with a compound represented by formula (II) under the action of a catalyst; a coupling reaction occurs between the two, and the reaction formula is as follows:

[0015]

[0016] Further, the structural formula of 3-mercaptopropionic acid ester is shown in the above formula (I), wherein R is methyl, ethyl, propyl, butyl, isobutyl or cyclohexyl. When R is selected from these groups, the structural formula of 3-mercaptopropionic acid ester is as follows:

[0017]

[0018] Furthermore, in the above formula (II), X is a leaving group, and X can be a group that easily leaves after contact with the compound of formula (I), such as chlorine, bromine, and iodine. When X is chlorine, bromine, and iodine, the compound of formula (II) can be prepared according to the literature: Journal of Agricultural and Food Chemistry (2008), 56(22), 10805-10810, and the method disclosed in patent CN101389625A.

[0019] Furthermore, the reaction of the compounds of formula (I) and formula (II) needs to be carried out in the presence of a catalyst, which can improve the reaction yield and selectivity. The catalyst is a phosphine ligand palladium catalyst, that is, a palladium salt and a phosphine ligand. The palladium salt is Pd(CH3CN)2Cl2, Pd(OAc)2, Pd(acac)2 or PdCl2, wherein Pd(acac)2 is di(acetylacetonate)palladium. In the palladium salt, palladium is divalent.

[0020] Furthermore, the phosphine ligand is a phosphine-containing bidentate ligand, which may be BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene), 1,3-bis(diphenylphosphine)propane or 1,2-bis(dimethylphosphine)ethane.

[0021] Furthermore, the molar ratio of the palladium salt to the compound represented by formula (II) is 0.002 to 0.01:1, for example, 0.002:1, 0.003:1, 0.004:1, 0.005:1, 0.006:1, 0.007:1, 0.008:1, 0.009:1, 0.01:1.

[0022] Furthermore, the molar ratio of the phosphine ligand to the compound represented by formula (II) is 0.004-0.02:1, for example, 0.004:1, 0.006:1, 0.008:1, 0.010:1, 0.012:1, 0.014:1, 0.016:1, 0.018:1, 0.02:1.

[0023] Furthermore, the molar ratio of the 3-mercaptopropionic acid ester represented by formula (I) to the compound represented by formula (II) is 1.03-1.2:1, for example, 1.03:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1.

[0024] Furthermore, an acid binder can be added to the reaction of the 3-mercaptopropionic acid ester represented by formula (I) and the compound represented by formula (II). The function of the acid binder is to remove the acid formed in the reaction and improve the efficiency of the reaction. The acid binder can be an acid binder reported in the prior art, such as K3PO4, K2HPO3, Na2CO3, K2CO3, Cs2CO3, etc., and each acid binder has a similar effect. The amount of the acid binder is sufficient to ensure that the by-product acid formed by the reaction can be completely removed.

[0025] Further, the reaction temperature of the 3-mercaptopropionic acid ester represented by formula (I) and the compound represented by formula (II) is 60-80°C, for example, 60°C, 70°C, 75°C, 80°C. Within this temperature range, the reaction can have a higher reaction efficiency and yield. Within this temperature range, the reaction time is generally 2-5h.

[0026] Furthermore, the reaction is carried out in a solvent, which provides a medium environment for the reaction, and any organic solvent that does not react with the raw materials can be used, and the solvent can be a nitrile solvent, a benzene solvent, an amide solvent, a ketone solvent, including but not limited to acetonitrile, toluene, N,N-dimethylformamide, acetone, etc. The amount of the solvent can be selected according to actual needs.

[0027] Furthermore, when synthesizing 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate in the present invention, it is only necessary to mix the raw materials, the catalyst and the solvent, and raise the temperature to a suitable reaction temperature for reaction. The reaction can occur without adjusting the pH and without gas protection. The operation is simple, the reaction conditions are mild, the post-treatment is simple, and the cost is low.

[0028] Furthermore, during the reaction, the progress of the reaction is detected by HPLC, and the reaction is terminated when the compound represented by formula (II) is detected to be less than 1%. The reaction solution after the reaction is cooled to room temperature, the catalyst is filtered to remove, and the reaction solution is distilled under reduced pressure. A solvent and water are added to extract the liquid, and the oil phase is distilled under reduced pressure to obtain an oily substance of 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate, and the post-treatment operation is simple.

[0029] The present invention also provides the use of the 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate as a sulfonepyraclostrobin intermediate. Experimental verification shows that the 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate can replace 5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate hydrochloride, and undergoes a condensation reaction with 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol and formaldehyde in an alkaline water environment to obtain an intermediate A. The use of 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate can avoid the generation of ammonia nitrogen wastewater and simplify the process. In addition, the reaction conditions are mild, the reaction selectivity is high, the post-treatment is simple and extensive, and the product yield is high, which is more suitable for industrial production.

[0030] When 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate is used as an intermediate, the synthetic route of sulfonepyraclostrobin is as follows:

[0031]

[0032] Compared with the prior art, the present invention has the following advantages:

[0033] 1. The present invention provides a new intermediate of sulfonepyraclostrobin. The use of 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate avoids many shortcomings of the 5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate intermediate, avoids the generation of ammonia nitrogen wastewater in the synthesis process of sulfonepyraclostrobin, is environmentally friendly, simplifies the synthesis process of sulfonepyraclostrobin, and has mild reaction conditions, high reaction selectivity, simple and extensive post-treatment, high yield of sulfonepyraclostrobin product, high economic value and environmental value, and is more suitable for industrial production.

[0034] 2. The synthesis method of 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate of the present invention is simple and efficient, has a fast reaction speed, high reaction selectivity, an extensive reaction process, mild reaction conditions, does not require excessively high temperature and high pressure, has low equipment requirements, low impurity content, high product yield and high purity, and has good prospects for industrial application. DETAILED DESCRIPTION

[0035] The present invention is further described below in conjunction with specific embodiments. The following description is only exemplary and does not limit the scope of protection. Other implementation schemes obtained by those skilled in the art without creative work without departing from the inventive concept of the present invention are also within the scope of protection.

[0036] In the following examples, unless otherwise specified, all raw materials used are commercially available products.

[0037] In the following examples, unless otherwise specified, the concentrations are all in mass percentage.

[0038] In the following examples, yield = actual mass of product × purity / theoretical mass of product.

[0039] In the following examples, the purity of the raw material 3-mercaptopropionic acid ester and the compound of formula (II) was 98%, and the purity of the Pd catalyst, the phosphine ligand, and K3PO4 was 99%.

[0040] Example 1

[0041] At room temperature, 10.63 g of methyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 1.24 g of K3PO42, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 80°C and stirred for reaction. After 2 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 17.53 g of oily substance was obtained, which was 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the product purity was 93%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 90.87%.

[0042] Example 2

[0043] At room temperature, 10.63 g of methyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 21.24 g of K3PO4, and 60 g of toluene were added to a four-necked bottle, and then heated to 80°C and stirred for reaction. After 2 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and 30 g of water was added to separate the mixture. The toluene was evaporated under reduced pressure from the oil phase to obtain 17.44 g of an oily substance after constant weight, which was 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the purity of the product was 91%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 88.46%.

[0044] Example 3

[0045] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 1, except that 60 g of acetonitrile was replaced by 60 g of DMF. The obtained oil product was 17.60 g, i.e., 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the purity of the product was 90%, and the yield was 88.29% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0046] Example 4

[0047] 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate was prepared according to the method of Example 1, except that: after heating to 70°C and stirring for 4 hours, the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole content was detected by HPLC to be <1%, and the reaction was terminated. The obtained oily product was 17.62 g, that is, 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the product purity was 92%, and the yield was 90.35% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0048] Example 5

[0049] 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate was prepared according to the method of Example 1, except that: after heating to 60°C and stirring for 5 hours, the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole content was detected by HPLC to be <1%, and the reaction was terminated. The obtained oily product was 17.53 g, that is, 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the product purity was 93%, and the yield was 90.87% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0050] Example 6

[0051] At room temperature, 8.41 g of methyl 3-mercaptopropionate, 15 g of 3-iodo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.17 g of Pd(CH3CN)2Cl2, 0.82 g of BINAP, 16.81 g of K3PO4, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-iodo-5,5-dimethyl-4,5-dihydroisoxazole was detected by HPLC and was less than 1%, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, and the liquids were separated. Toluene was evaporated under reduced pressure from the organic phase to obtain 13.74 g of an oily substance after constant weight, which was 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the purity of the product was 92%, and the yield based on 3-iodo-5,5-dimethyl-4,5-dihydroisoxazole was 89.06%.

[0052] Example 7

[0053] At room temperature, 16.19 g of methyl 3-mercaptopropionate, 15 g of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.29 g of Pd(CH3CN)2Cl2, 1.38 g of BINAP, 28.31 g of K3PO4, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 22.5 g of an oily substance was obtained, which was 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the product purity was 92%, and the yield based on 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was 86.57%.

[0054] Example 8

[0055] At room temperature, 13.57 g of ethyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 1.24 g of K3PO42, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, the liquids were separated, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 18.51 g of an oily substance was obtained, which was ethyl 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl)propionate. After testing, the purity of the product was 91%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 88.19%.

[0056] Example 9

[0057] At room temperature, 14.99 g of propyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 21.24 g of K3PO4, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 19.69 g of an oily substance was obtained, which was propyl 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl)propionate. After testing, the purity of the product was 92%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 89.42%.

[0058] Example 10

[0059] At room temperature, 16.4 g of butyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 1.24 g of K3PO42, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 60 g of water were added to the oily substance, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 19.98 g of an oily substance was obtained, which was butyl 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl)propionate. After testing, the product purity was 93%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 86.77%.

[0060] Embodiment 11

[0061] At room temperature, 16.4 g of isobutyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 0.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 21.24 g of K3PO4, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 19.85 g of an oily substance was obtained, which was isobutyl 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl)propionate. After testing, the purity of the product was 92%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 85.27%.

[0062] Example 12

[0063] At room temperature, 19.04 g of cyclohexyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 20.22 g of Pd(CH3CN)2Cl2, 1.04 g of BINAP, 21.24 g of K3PO4, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60°C and stirred for reaction. After 5 hours, when the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was <1% as detected by HPLC, the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. 60 g of toluene and 30 g of water were added to the oily substance, and toluene was evaporated under reduced pressure from the organic phase. After constant weight, 21.73 g of an oily substance was obtained, which was cyclohexyl 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl)propionate. After testing, the purity of the product was 92%, and the yield based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was 84.83%.

[0064] Example 13

[0065] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 0.22g of Pd(CH3CN)2Cl2 was replaced by 0.14g of Pd(OAc)2. The obtained oil product was 17.55g, that is, 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the product purity was 89%, and the yield was 87.06% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0066] Embodiment 14

[0067] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 0.22g of Pd(CH3CN)2Cl2 was replaced by 0.25g of Pd(acac)2. The obtained oil product was 17.0g, that is, 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the product purity was 90%, and the yield was 85.28% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0068] Embodiment 15

[0069] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 0.22g of Pd(CH3CN)2Cl2 was replaced by 0.15g of PdCl2. The obtained oil product was 17.21g, that is, 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the purity of the product was 91%, and the yield was 87.29% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0070] Example 16

[0071] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 1.04 g of BINAP was replaced with 0.96 g of Xantphs. The obtained oil product was 17.33 g, i.e., 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the product purity was 88%, and the yield was 85% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0072] Embodiment 17

[0073] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 1.04 g of BINAP was replaced with 0.688 g of 1,3-bis(diphenylphosphine)propane. The obtained oil product was 17.03 g, i.e., 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the product purity was 90%, and the yield was 85.43% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0074] Embodiment 18

[0075] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 1.04 g of BINAP was replaced with 0.250 g of 1,2-bis(dimethylphosphine)ethane. The obtained oil product was 17.15 g, i.e., 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the product purity was 91%, and the yield was 86.99% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0076] Embodiment 19

[0077] 1. Synthesis of intermediate A:

[0078] At room temperature, 40 mL of water, 11.8 g of sodium hydroxide, 20 g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol and 10.6 g of 37 wt % formaldehyde aqueous solution were added to a four-necked bottle in sequence. After stirring for 2 hours, 29.3 g of methyl 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was added at 10° C., and then the reaction was continued at this temperature. After 7 hours, HPLC detection showed that the content of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was <1%, and the reaction was completed. 45.5 g of 37 wt % hydrochloric acid was added to the reaction solution, and then stirred for crystallization. A white solid precipitate was obtained by suction filtration. After drying, 36.5 g of solid was obtained, which was intermediate A. The purity was 90.8% as determined by HPLC, and the yield was 91.3% based on 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol.

[0079] 2. Synthesis of intermediate B:

[0080] 14.4 g of intermediate A, 6.9 g of potassium carbonate and 40 ml of ethanol were added to a four-necked bottle, and the reaction was carried out at 20°C for 2 h. 8.5 g of Freon gas was introduced under normal pressure and the reaction was carried out for 8 h. The content of intermediate A was <1% as determined by HPLC. After the reaction, the pH was adjusted to 7, the solid was removed by filtration, and the ethanol was removed after desolventizing. 30 mL of toluene and 15 mL of water were added, and the liquids were separated. The mother liquor was the oil phase, and 15.19 g of an oily substance was obtained. The purity was 88% as determined by HPLC, and the yield based on intermediate A was 87%.

[0081] 3. Synthesis of sulfonepyraclostrobin:

[0082] At room temperature, 40 ml of acetic acid and 28.3 g of 30 wt% hydrogen peroxide were added to the oily substance in step 2. After stirring for 1 hour, the temperature was slowly raised to 60°C for reaction. After 4 hours, HPLC detection showed that the content of intermediate B was <1%. After vacuum concentration to remove acetic acid, the reaction solution was cooled to room temperature and filtered to obtain 13.1 g of white solid, which was sulfonepyraclostrobin. The content was 98.4% after detection. Based on intermediate B, the yield of sulfonepyraclostrobin was 88.5%.

[0083] Comparative Example 1

[0084] At room temperature, 10.63 g of methyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound shown in formula (II)), and 4.00 g of NaOH were added to a four-necked bottle, and then heated to 60°C for stirring and reacting. After 5 hours, HPLC was used to detect that there was no residual raw material, and the reaction was completed. The reaction solution was cooled to room temperature, water was added to separate, and the oil phase was evaporated under reduced pressure to remove the solvent. After separation through a silica gel column, 9.13 g of an oily substance was obtained, which was 3-(5,5-dimethyl-4,5-dihydroisoxazole-3-yl) propionate. After testing, the product purity was 95%, and the yield was 48.34% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.

[0085] Comparative Example 2

[0086] At room temperature, 10.63 g of methyl 3-mercaptopropionate, 15 g of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (compound represented by formula (II)), 1.04 g of BINAP, 21.24 g of K3PO4, and 60 g of acetonitrile were added to a four-necked bottle, and then heated to 60° C. and stirred for reaction. After 5 hours, HPLC detection showed that there was almost no reaction, indicating the reaction was completed.

[0087] Comparative Example 3

[0088] 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate was prepared according to the method of Example 5, except that 1.04g of BINAP was replaced with 0.22g of triphenylphosphine. The obtained oil product was 13.12g, that is, 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate. After testing, the purity of the product was 86%, and the yield was 62.89% based on 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole. It can be seen that the yield is significantly reduced when the phosphine ligand BINAP in Example 5 is replaced with triphenylphosphine.

Claims

1. A method for synthesizing 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionate, characterized in that: The 3-mercaptopropionic acid ester represented by formula (I) and the compound represented by formula (II) are subjected to a coupling reaction in the presence of a catalyst to obtain the 3-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) propionic acid ester represented by formula (III); In formula (I) and formula (III), R is methyl, ethyl, propyl, butyl, isobutyl or cyclohexyl; in formula (II), X is a leaving group; The catalyst is a palladium salt and a phosphine ligand, the palladium salt is Pd(CH3CN)2Cl2, Pd(OAc)2, Pd(acac)2 or PdCl2, and the phosphine ligand is BINAP, Xantphos, 1,3-bis(diphenylphosphine)propane or 1,2-bis(dimethylphosphine)ethane.

2. The synthesis method according to claim 1, characterized in that: In formula (II), X is chlorine, bromine or iodine.

3. The synthesis method according to claim 1, characterized in that: The molar ratio of the palladium salt to the compound represented by formula (II) is 0.002-0.01:1; the molar ratio of the phosphine ligand to the compound represented by formula (II) is 0.004-0.02:

1.

4. The synthesis method according to claim 1, characterized in that: The reaction is carried out in the presence of an acid binding agent.

5. The synthesis method according to claim 4, characterized in that: The acid binding agent is selected from K3PO4, K2HPO3, Na2CO3, K2CO3, and Cs2CO3.

6. The synthesis method according to any one of claims 1 to 5, characterized in that: The molar ratio of the 3-mercaptopropionic acid ester represented by formula (I) to the compound represented by formula (II) is 1.03-1.2:

1.

7. The synthesis method according to any one of claims 1 to 5, characterized in that: The reaction temperature of the 3-mercaptopropionic acid ester represented by formula (I) and the compound represented by formula (II) is 60-80°C.

8. The synthesis method according to any one of claims 1 to 5, characterized in that: The reaction is carried out in a solvent.

9. The synthesis method according to claim 8, characterized in that: The solvent is a nitrile solvent, a benzene solvent, an amide solvent or a ketone solvent.

10. The synthesis method according to claim 9, characterized in that: The solvent is acetonitrile, toluene, N,N-dimethylformamide or acetone.

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