Preparation method for improving purity of 3-dichloromethyl-1-substituted pyrazole compound

Abstract

The invention discloses a preparation method for improving the purity of a 3-dichloromethyl-1-substituted pyrazole compound, which comprises the following steps: introducing an organic nitrogen-containing weak base (such as aromatic tertiary amine) and dialkylamine, and changing the organic nitrogen-containing weak base halogen acid salt into a free organic nitrogen-containing weak base by utilizing the alkalinity strong and weak relationship between the organic nitrogen-containing weak base and the dialkylamine, so as to improve the purity of the 3-dichloromethyl-1-substituted pyrazole compound. And forming an alkaline cosolvent with a water-insoluble aprotic solvent 1, and simultaneously co-producing an aqueous solution of dialkylamine halogen acid salt. The isomer generated in the cyclization reaction process is completely controlled, the total yield of the three-step reaction of condensation, dissociation and cyclization reaches 95% or above, and a high-purity product can be obtained without refining.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticide synthesis, in particular to a preparation method for improving the purity of 3-dichloromethyl-1-substituted pyrazole compounds. BACKGROUND

[0002] 3-dichloromethyl-1-substituted pyrazole compounds are a class of organic compounds with specific structures and potential application value, and have biological activities such as antibacterial, anti-inflammatory, and antitumor activities.

[0003] Some derivatives have been applied to the synthesis routes of various important products, such as 3-dichloromethyl-1H-methyl pyrazole-4-carboxylic acid ethyl ester, the English name of which is 3-(dichloromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester; the molecular weight is 237.08; the CAS is 851725-87-6; and the structural formula is as shown below. The compound is an important intermediate of a fungicide (Bixafen) developed by Bayer Company, a fungicide (Fluxapyroxad) developed by BASF Company, and a fungicide (Isopyrazam) developed by Syngenta Company. Pyrazole amide fungicides are an important new type of fungicide, and relevant products have been put on the market, which has become a new hotspot for the development of fungicides.

[0004] The patent document with the publication number US20060252944A1 discloses a preparation method of 3-dichloromethyl-1H-methyl pyrazole-4-carboxylic acid ethyl ester, in which, under alkaline conditions, dichloroacetyl chloride and dimethylamino acrylate are used as raw materials, a reaction is performed to generate 2-(dichloroacetyl)-3-(dimethylamino) acrylate, and then a cyclization is performed with a hydrazine compound under low-temperature conditions to obtain a crude product, wherein the proportion of the main product 3-dichloromethyl-1H-methyl pyrazole-4-carboxylic acid ethyl ester and the by-product 5-dichloromethyl-1H-methyl pyrazole-4-carboxylic acid ethyl ester is 93.8:6.2, and such a high proportion of isomers poses great challenges to product yield and purification. At present, the post-treatment method of the condensation step reported by the patent using this process route is generally to dissolve with water, remove the aqueous phase by layering, or use a filtration scheme to remove the acid-binding agent hydrogen halide salt, but the treatment scheme of brine or waste salt is not mentioned.

[0005] Patent document WO2012176717A1 discloses a preparation method of pyrazole compounds, which uses dihaloacetyl halide and 3-dialkylamino acrylate as raw materials to generate intermediate 2-dihaloacetyl-3-dialkylamino acrylate, and only needs to add inorganic base to the system to directly perform cyclization reaction without removing acid-binding agent hydrogen halide salt in the system, so that high-selectivity target product can be obtained. This method solves the problem of isomers to some extent, but the free acid-binding agent (triethylamine) is mostly dissolved in water phase, and the basicity of the basic co-solvent formed by the triethylamine and aprotic solvent is not enough, so the best effect cannot be achieved, and when two halogens are both replaced by chlorine, if triethylamine is used as the acid-binding agent, the strong basicity of the triethylamine will cause dihaloacetyl chloride to be unstable and easy to generate enone structure, so the single-step yield of the condensation reaction is lower than 50%.

[0006] Chinese patent document CN102718712A discloses a preparation method of 3-polyhalomethyl-1H-methyl pyrazole-4-nitrile, which comprises: adding dihaloacetyl halide and polyhaloacetyl chloride to generate 2-polyhaloacyl-3-dialkylamino acrylate, and then performing cyclization reaction with methyl hydrazine to obtain 3-polyhalomethyl-1H-methyl pyrazole-4-nitrile, but the 3-polyhalomethyl-1H-methyl pyrazole-4-nitrile obtained still contains isomers substituted at position 5, and the yield is low.

[0007] The existing methods cannot completely solve the problem of impurities of isomers 5-dichloromethyl-1H-substituted pyrazole compounds, and further purification is needed to obtain qualified 3-dichloromethyl-1H-substituted pyrazole compounds. Since the isomers cannot be easily removed from the product, although the purification step is increased, the product quality cannot be completely guaranteed, and the production cost is also increased. Therefore, it is urgent to find a preparation method for improving the purity and yield of 3-dichloromethyl-1-substituted pyrazole compounds. SUMMARY

[0008] To solve the above technical problems, the present application provides a preparation method for improving the purity of 3-dichloromethyl-1-substituted pyrazole compounds, which uses an organic nitrogen-containing weak base with pKa<7 as an acid-binding agent, and adds a free step after the condensation reaction to introduce dialkylamine to make the hydrogen halide salt of the organic nitrogen-containing weak base become free organic nitrogen-containing weak base, and form a basic co-solvent with water-insoluble aprotic solvent 1, thereby increasing the solubility of 2-dichloroacetyl-3-(dialkylamino) acrylate under low temperature conditions, improving the reaction speed and regioselectivity of the cyclization reaction, and obtaining a product with high content by the cyclization reaction, so that the isomers are completely controlled and further purification is not needed, and the total yield of the three steps of condensation, free and cyclization can reach more than 95%.

[0009] A preparation method for improving the purity of 3-dichloromethyl-1-substituted pyrazole compounds, comprising the following steps: In water-insoluble aprotic solvent 1, 3-dialkylamino acryl compound (II) is subjected to condensation reaction with dichloroacetyl halide (I) by using organic nitrogen-containing weak base (III) as an acid-binding agent to obtain a mixture of 2-dichloroacetyl-3-(dialkylamino) acryl compound (IV) and hydrogen halide salt of the organic nitrogen-containing weak base (V), and then, the mixture is added with dialkylamine (VI) to perform ionization reaction, and then, the mixture is separated into layers, and the basic co-solvent solution (a mixture of water-insoluble aprotic solvent 1, IV and III) of 2-dichloroacetyl-3-(dialkylamino) acryl compound is collected; and then, the obtained basic co-solvent solution of 2-dichloroacetyl-3-(dialkylamino) acryl compound is dropped into a mixed solution of hydrazine compound (VIII), water-soluble base and water-insoluble aprotic solvent 2 to perform cyclization reaction, and thus, 3-dichloromethyl-1-substituted pyrazole compound (IX) is obtained.

[0010] The specific route is as follows: In the present application, the organic nitrogen-containing weak base (III) with pKa<7 is used as the acid-binding agent, and the basicity thereof is moderate, which can not only avoid the influence of the excessive basicity of the acid-binding agent on the stability of dichloroacetyl halide, but also can combine the generated hydrogen halide into hydrogen halide salt of the organic nitrogen-containing weak base quickly, so that the incomplete absorption of hydrogen halide in the system is avoided, and the raw material 3-dialkylamino acryl compound is not easily self-polymerized under the action of the unabsorbed hydrogen halide, for example, 3-dialkylamino acrylate is easily polymerized into trisalkyl trimellitate, and the yield is obviously reduced.

[0011] Meanwhile, by adding the aqueous solution of dialkylamine (VI) after the condensation reaction, the hydrogen halide salt of the organic nitrogen-containing weak base (V) generated in the condensation reaction is converted into the free organic nitrogen-containing weak base (III) by using the weak basicity of the organic nitrogen-containing weak base (pKa<7 and insoluble in water) (III) compared with that of dialkylamine (VI), and the hydrogen halide salt of dialkylamine (VII) is co-produced, and the basic co-solvent is formed by the organic nitrogen-containing weak base (III) and water-insoluble aprotic solvent 1. Due to the existence of the basic co-solvent (a mixed system of the organic nitrogen-containing weak base and aprotic solvent 1), the solubility of 2-dichloroacetyl-3-(dialkylamino) acryl compound (IV) is increased at low temperature, and the reaction speed and regioselectivity of the subsequent cyclization reaction are improved, the content of the product obtained by the cyclization reaction is high, the isomer is completely controlled, and no further purification is needed, and the total yield of the three steps of condensation, ionization and cyclization can reach more than 95%.

[0012] Preferably, the preparation method of the 3-dialkylamino acryl compound (II) is that the 3-hydroxy acryl compound sodium salt (X) is reacted with a dialkylamine hydrohalide aqueous solution (VII) to obtain the 3-dialkylamino acryl compound (II).

[0013] The specific route is as follows: Further preferably, the structure of the 3-dialkylamino acryl compound (II) is as follows, wherein R1 and R2 are each independently selected from C1-C4 alkyl; R3 is COOR4 or CN; and R4 is C1-C4 alkyl.

[0014] Preferably, the water-insoluble aprotic solvent 1 and the water-insoluble aprotic solvent 2 are each at least one of an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an alkane, a halogenated alkane, a cycloalkane, an ether solvent, an ester solvent, and a nitrile solvent.

[0015] In the present application, the aromatic hydrocarbon can be toluene, o-xylene, m-xylene, ethylbenzene, diethylbenzene (o-, m-, p-), 1,3,5-trimethylbenzene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, cumene, propylbenzene, p-methylcumene, 1,2,3,5-tetramethylbenzene, butylbenzene, sec-butylbenzene, tert-butylbenzene, isobutylbenzene, amylbenzene, tert-amylbenzene, diamylbenzene, 1-methylnaphthalene, tetrahydronaphthalene, decahydronaphthalene, and the like.

[0016] The halogenated aromatic hydrocarbon can be chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, o-chlorotoluene, m-chlorotoluene, bromobenzene, o-bromotoluene, m-bromotoluene, m-bromochlorobenzene, 4-chlorobenzotrifluoride, fluorobenzene, benzotrifluoride, and the like.

[0017] The alkane can be 2-methylbutane, pentane, hexane, 2,3-dimethylbutane, 2,2-dimethylbutane, 3-methylpentane, 2-methylpentane, heptane, octane, 2,2,3-trimethylpentane, 2,3,4-trimethylpentane, 2,2,4-trimethylpentane, nonane, and the like.

[0018] The halogenated alkane can be dichloromethane, trichloromethane, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1-chloropropane, 1,3-dichloropropane, 1-chlorobutane, 2-chlorobutane, 1,4-dichlorobutane, 2-chloro-2-methylbutane, 1-chloro-3-methylbutane, 1,5-dichloropentane, chlorohexane, 1-chloro-2-ethylhexane, dibromomethane, bromopropane, 2-bromopropane, 1,3-dibromopropane, 1,2-dibromopropane, 2-bromobutane, bromobutane, 1-bromo-2-methylpropane, 2-bromo-2-methylpropane, bromopentane, bromohexane, bromoheptane, 1-iodopropane, 2-iodopropane, 2-iodobutane, 1-iodo-2-methylpropane, 1-iodopentane, 1-iodo-3-methylbutane, chlorobromomethane, bromodichloromethane, chlorodibromomethane, and the like.

[0019] The cycloalkane can be cyclopentane, cyclohexane, methylcyclopentane, methylcyclohexane, cycloheptane, ethylcyclohexane, 1,3-dimethylcyclohexane, 1,2-dimethylcyclohexane, cyclooctane, butylcyclohexane, and the like.

[0020] The ether solvent can be diethyl ether, diisopropyl ether, di-n-propyl ether, di-n-butyl ether, methyl n-butyl ether, methyl t-butyl ether, diisopentyl ether, diisohexyl ether, anisole, phenyl ethyl ether, methoxytoluene (ortho, meta, para), benzyl methyl ether, benzyl ethyl ether, ethylene glycol dibutyl ether, diethylene glycol dibutyl ether, hexamethyldisiloxane, and the like.

[0021] The ester solvent can be ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl butyrate, ethyl butyrate, propyl butyrate, butyl butyrate, methyl valerate, ethyl valerate, propyl valerate, butyl valerate, methyl hexanoate, ethyl hexanoate, propyl hexanoate, butyl hexanoate, methyl benzoate, ethyl benzoate, and the like.

[0022] The nitrile solvent can be propionitrile, butyronitrile, isobutyronitrile, valeronitrile, benzonitrile, phenylacetonitrile, 3-methoxypropionitrile, 3-dimethylaminopropionitrile, and the like.

[0023] In the present application, the aprotic solvent 1 and the aprotic solvent 2 can be the same solvent or different solvents, and are preferably the same solvent.

[0024] Preferably, the organic nitrogen-containing weak base is one of an aromatic tertiary amine compound, a pyridine compound, a quinoline compound, an imidazole compound, a pyrazine compound, or a combination of at least two thereof, having a pKa less than 7 and being insoluble in water.

[0025] Further preferably, the organic nitrogen-containing weak base is N,N-dimethylaniline, N,N-diethylaniline, pyridine, 2-methylpyridine.

[0026] In the present application, when the organic nitrogen-containing weak base is N,N-dimethylaniline, N,N-diethylaniline, pyridine or 2-methylpyridine, the pKa is between 5.0 and 6.0, which ensures that dichloroacetyl halide has good stability therein and can quickly combine with the generated hydrogen halide, thereby ensuring that the raw material can be efficiently converted into the target product.

[0027] Further preferably, the mass ratio of the water-insoluble aprotic solvent 1, the water-insoluble aprotic solvent 2 and the organic nitrogen-containing weak base is 5-15:5-15:1.

[0028] Preferably, the molar ratio of the organic nitrogen-containing weak base, the 3-dialkylamino acryl compound and the dichloroacetyl halide is 1-4:1:1-2.

[0029] Further preferably, the molar ratio of the organic nitrogen-containing weak base, the 3-dialkylamino acryl compound and the dichloroacetyl halide is 1-1.2:1:1-1.2.

[0030] Preferably, the temperature of the condensation reaction is -30-60℃.

[0031] Preferably, the dialkylamine has the following structure: wherein R1 and R2 are each independently selected from C1-C4 alkyl; and the dialkylamine is a 20%-80% dialkylamine aqueous solution.

[0032] In the present application, the dialkylamine (Ⅵ) is an aliphatic secondary amine, and the pKa value is basically between 10.5 and 11.5; the pKa value of the organic nitrogen-containing weak base (Ⅲ) selected in the present application is less than 7, and the organic nitrogen-containing weak base (Ⅲ) with weaker basicity is dissociated into an organic phase by using the stronger basicity of the dialkylamine (Ⅵ), and an aqueous solution of dialkylamine hydrogen halide salt (Ⅶ) is co-produced.

[0033] Preferably, the molar ratio of the organic nitrogen-containing weak base and the dialkylamine is 1:1-4.

[0034] Preferably, the temperature of the dissociation reaction is -30-80℃.

[0035] Preferably, the aqueous phase after the dissociation reaction is the aqueous solution of dialkylamine hydrogen halide salt (Ⅶ), which is reused in the preparation of the 3-dialkylamino acryl compound.

[0036] Preferably, the water-soluble base is an inorganic water-soluble base or an organic water-soluble base.

[0037] In the present application, the inorganic water-soluble base can be potassium hydroxide, sodium hydroxide, cesium hydroxide, rubidium hydroxide, etc., and the organic water-soluble base can be guanidine, 1,1-dimethylguanidine, 1,3-dimethylguanidine, tetramethylguanidine, 1,1-diethylguanidine, 1,3-diethylguanidine, tetraethylguanidine, tetramethylammonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium hydroxide, hexadecyltrimethylammonium hydroxide, choline hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.

[0038] Preferably, the molar ratio of the water-soluble base and the 2-dichloroacetyl-3-(dialkylamino) propene compound is 0.1-1:1.

[0039] In the present application, the basic co-solvent solution is a mixed system of the 2-dichloroacetyl-3-(dialkylamino) propene compound (IV), the organic nitrogen-containing weak base (III), and the water-insoluble aprotic solvent 1. The organic nitrogen-containing weak base and the water-insoluble aprotic solvent 1 can form a basic co-solvent system, which can greatly improve the solubility of the 2-dichloroacetyl-3-(dialkylamino) propene compound (IV) under low-temperature conditions, so that the 2-dichloroacetyl-3-(dialkylamino) propene compound (IV) can be completely dissolved in the basic co-solvent under low-temperature conditions. In combination with the basic effect of the water-soluble base, the rate and regioselectivity of the cyclization reaction can be improved, and the high-purity target product (IX) free of isomers can be obtained.

[0040] Preferably, the basic co-solvent solution is first cooled to -40-20 ℃, and then the mixed solution of the hydrazine compound, the water-soluble base, and the water-insoluble aprotic solvent 2 is added dropwise.

[0041] Further preferably, the basic co-solvent solution is first cooled to -20-0 ℃, and then the mixed solution of the hydrazine compound, the water-soluble base, and the water-insoluble aprotic solvent 2 is added dropwise.

[0042] Preferably, the temperature of the cyclization reaction is -50-0 ℃.

[0043] Preferably, the structure of the hydrazine compound is as shown below: wherein R5 is selected from H, C1-C4 alkyl, or cycloalkyl.

[0044] In the present application, the above hydrazine compounds can be obtained by purchase, and different 3-dichloromethyl-1-substituted pyrazole compound products can be obtained by replacing hydrazine compounds with different R5 substitutions. Preferably, the hydrazine compound is a 20%-80% hydrazine compound aqueous solution.

[0045] Preferably, the molar ratio of the hydrazine compound and the 2-dichloroacetyl-3- (dialkylamino) propene compound is 1-4:1.

[0046] In the present application, excess hydrazine compound still exists in the aqueous phase, and after distilling the dialkylamine, the remaining aqueous phase containing the hydrazine compound can be reused in the cyclization reaction after treatment.

[0047] Preferably, the dialkylamine (VIII) recovered after the cyclization reaction is reused in the free reaction.

[0048] Preferably, the total yield of the three-step condensation, free and cyclization reactions reaches more than 95%.

[0049] The present application also provides the 3-dichloromethyl-1-substituted pyrazole compound prepared by the above method, and the purity of the 3-dichloromethyl-1-substituted pyrazole compound reaches more than 99%.

[0050] Preferably, the structure of the 3-dichloromethyl-1-substituted pyrazole compound is as follows: wherein R3 is COOR4, CN; R4 is C1-C4 alkyl; R5 is selected from H, C1-C4 alkyl or cycloalkyl.

[0051] Compared with the prior art, the present application has the following advantages: (1) The present application introduces an organic weak base containing nitrogen (such as aryl tertiary amine), which solves the problems of instability of dichloroacetyl halide caused by excessive alkalinity of the acid-binding agent in the prior art or reduced yield caused by self-polymerization of the raw material due to insufficient alkalinity of the acid-binding agent. At the same time, by using the difference in alkalinity between the organic weak base containing nitrogen and the dialkylamine, the dialkylamine is introduced after the condensation reaction, the hydrogen halide salt of the organic weak base containing nitrogen is converted into the free state of the organic weak base containing nitrogen, and forms a basic co-solvent solution with the water-insoluble aprotic solvent 2-dichloroacetyl-3- (dialkylamino) propene compound (IV), while the aqueous solution of the dialkylamine hydrogen halide salt is co-produced. The isomers generated during the cyclization reaction are completely controlled, the total yield of the three-step condensation, free and cyclization reactions reaches more than 95%, and high-purity products can be obtained without refining.

[0052] (2) The present application realizes the recycling of the by-product dialkylamine and hydrogen halide, and the secondary use of the acid-binding agent through the free reaction, which greatly reduces the amount of recovery and waste, and conforms to the concept of green synthesis.

[0053] (3) The preparation method of the present application has high atom economy, is convenient to use, and is suitable for industrial production. Attached Figure Description

[0054] Figure 1 and 2 The images show the gas chromatogram and hydrogen nuclear magnetic resonance (NMR) spectrum of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate prepared in Example 1.

[0055] Figure 3 The gas chromatogram of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate prepared in Example 2 is shown.

[0056] Figure 4 and 5 The images show the liquid chromatography and hydrogen nuclear magnetic resonance spectra of 3-dichloromethyl-1H-methylpyrazole-4-carboxynitrile prepared in Example 5.

[0057] Figure 6 The gas chromatogram of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate prepared in Comparative Example 1 is shown. Detailed Implementation

[0058] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0059] All raw materials used in this invention are commercially available.

[0060] Example 1 (1) Preparation of ethyl 3-dimethylaminoacrylate Xylene, 6.9 g of cerium trichloride, and an aqueous solution of dimethylamine hydrochloride (containing 815 g of dimethylamine hydrochloride derived from the aqueous phase co-produced in the free step) were added to a reaction flask. The mixture was cooled to below -10 °C, and a xylene solution of sodium ethyl 3-hydroxyacrylate (containing 1380 g of sodium ethyl 3-hydroxyacrylate) was added. After the addition was complete, the mixture was kept at 0 °C for 5 hours. The mixture was allowed to separate into layers. The xylene was recovered by vacuum distillation of the organic phase and reused. The product, ethyl 3-dimethylaminoacrylate, was then obtained by high-vacuum distillation. The gas phase content was 99.35%, and the yield was 96.3%.

[0061] (2) Condensation and free reactions Into a four-necked flask, 3-dimethylamino acrylate ethyl ester 143.2 g and 670 g of toluene were added under nitrogen protection, and the temperature was lowered to 0 ℃. Dichloroacetyl chloride 154.7 g and N,N-dimethylaniline 133.3 g were respectively loaded into two dropping funnels, and were dropped into the reaction flask while maintaining the temperature at 0-5 ℃. After the dropping was completed, the reaction was maintained for 1 h. During the reaction, solid gradually precipitated. After the reaction was completed, 40% dimethylamine aqueous solution (containing dimethylamine 49.6 g) was added to the system while maintaining the temperature at 10-20 ℃. After the addition was completed, the system was stirred for 0.5 h. At this time, no solid existed in the system, and the system was separated into two layers. The aqueous phase mainly contained dimethylamine hydrochloride, which could be reused in step (1). The basic co-solvent solution of 2-dichloroacetyl-3-(dimethylamino) acrylate ethyl ester was collected, and was directly used in the cyclization reaction without treatment.

[0062] (3) Preparation of 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester Into a four-necked flask, 40% methylhydrazine 345.5 g, sodium hydroxide 16 g, and 720 g of toluene were added, and the temperature was lowered to -30 ℃. The basic co-solvent solution (containing 2-dichloroacetyl-3-(dimethylamino) acrylate ethyl ester 254.1 g, N,N-dimethylaniline 133.3 g, and toluene 670 g) was lowered to about -10 ℃.

[0063] The temperature was maintained at -30 to -25 ℃, and the lowered basic co-solvent solution was added dropwise. After the addition was completed, the system was stirred for 0.5 h. After the reaction was completed, the system was separated into two layers. The dimethylamine in the aqueous phase was evaporated (absorbed with water, and directly recycled for the free reaction in step (2) without purification). The organic phase was first recovered by low vacuum to remove toluene and N,N-dimethylaniline, and then was evaporated by high vacuum to remove the product 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester 227.6 g, with a yield of 96.0%. The gas chromatogram of the obtained product is shown in Figure 1 . The content of 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester was 99.604%, the isomer 5-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester was not detected, and other impurities accounted for 0.396%. The nuclear magnetic hydrogen spectrum is shown in Figure 2 . 1 H NMR (600 MHz, CDCl3) δ 7.87(s, 1H), 7.41 (s, 1H), 4.32 (qd, J = 7.1, 1.6 Hz, 2H), 3.97 (d, J = 1.3 Hz, 3H),1.36 (td, J = 7.1, 1.5 Hz, 3H). Example 2 (1) Preparation of 3-dimethylamino acrylate ethyl ester The preparation method is the same as that in Example 1.

[0064] (2) Condensation and free reaction Under nitrogen protection, 3-dimethylamino acrylate 143.2 g and 1250 g of toluene were added into a four-necked flask, which was cooled to -10 ℃, and dichloroacetyl bromide 211.0 g and N,N-dimethyl-p-toluidine 155.5 g were respectively loaded into two dropping funnels, which were kept at -10~5 ℃, and then were simultaneously dropped into the reaction flask. After dropping, the reaction was kept for 1 hour. During the reaction, solid gradually precipitated. After the reaction was completed, 0~10 ℃ was kept, and 50% dimethylamine aqueous solution (containing dimethylamine 54.1 g) was added into the system. After the addition was completed, the system was stirred for 0.5 hours. At this time, no solid existed in the system, and the water phase mainly contained dimethylamine hydrobromide, which could be reused in step (1). The basic co-solvent solution of 2-dichloroacetyl-3-(dimethylamino) acrylate was collected, and could be directly used in the cyclization reaction without treatment.

[0065] (3) Preparation of 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester Into a four-necked flask, 45% methylhydrazine 358.3 g, potassium hydroxide 28.1 g, and 1400 g of toluene were added, and the temperature was lowered to -35 ℃. The basic co-solvent solution (containing 2-dichloroacetyl-3-(dimethylamino) acrylate 254.1 g, N,N-dimethyl-p-toluidine 155.5 g, and toluene 1250 g) was cooled to about -15 ℃.

[0066] The internal temperature was kept at -35~-30 ℃, and the cooled basic co-solvent solution was added dropwise. After the addition was completed, the system was stirred for 0.5 hours, and the reaction was completed. The system was separated into layers. The dimethylamine in the water phase was evaporated (absorbed by water, and directly recycled for the free reaction in step (2) without purification), and the organic phase was first recovered by low vacuum to recover toluene and N,N-dimethyl aniline, and then was evaporated by high vacuum to evaporate the product 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester 225.7 g, with a yield of 95.2%. The gas chromatogram of the obtained product is shown in Figure 3 , which shows that the content of 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester is 99.800%, the isomer 5-dichloromethyl-1H-methylpyrazole-4-carboxylic acid ethyl ester is not detected, and other impurities account for 0.200%.

[0067] Example 3 (1) Preparation of 3-dipropylamino acrylate Into a reaction flask, add xylene, cerium trichloride 6.5 g and aqueous solution of dipropylamine hydrofluoride (containing dipropylamine hydrofluoride 1212 g from the water phase of the co-production in the previous step), cool to below -10 ℃, add a solution of sodium salt of 3-hydroxybutyl acrylate in xylene (containing sodium salt of 3-hydroxybutyl acrylate 1662 g), after the addition, keep the temperature at 0 ℃ for 6 hours, separate the layers, recover xylene from the organic phase by distillation under reduced pressure, and then distill under high vacuum to obtain the product of 3-dipropylaminobutyl acrylate, with a gas phase content of 99.68%, and a yield of 95.8%.

[0068] (2) Condensation and dissociation reaction Under nitrogen protection, add 3-dipropylaminobutyl acrylate 227.4 g and dichloromethane 1930 g into a four-necked flask, cool to -20 ℃, load dichloroacetyl fluoride 120.9 g and 2-chloro-N,N-diethyl aniline 192.9 g into two dropping funnels respectively, keep the temperature at -20~-15 ℃, and drop into the reaction flask at the same time, after the dropping, keep the temperature for 1 hour, during the reaction, solid gradually precipitates. After the reaction is completed, keep the temperature at -10~0 ℃, add 30% aqueous solution of dipropylamine (containing dipropylamine 106.2 g) into the system, after the addition, stir for 0.5 hours, at this time, there is no solid in the system, separate the layers, the aqueous phase mainly contains dipropylamine hydrofluoride, which can be used in step (1). Collect the basic co-solvent solution containing 2-dichloroacetyl-3-(dipropylamino) butyl acrylate, which can be directly used for cyclization reaction without treatment.

[0069] (3) Preparation of 3-dichloromethyl-1H-methylpyrazole-4-butyrate Into a four-necked flask, add 35% methylhydrazine 526.5 g, tetramethylguanidine 51.8 g, dichloromethane 1930 g, cool to -25 ℃, and cool the basic co-solvent solution (containing 2-dichloroacetyl-3-(dipropylamino) butyl acrylate 338.3 g, 2-chloro-N,N-diethyl aniline 192.9 g, dichloromethane 1930 g) to about -5 ℃.

[0070] Keep the internal temperature at -25~-20 ℃, add the cooled basic co-solvent solution, after the addition, keep stirring for 0.5 hours, the reaction is completed, separate the layers. Distill dipropylamine from the aqueous phase (absorb with water, no need for purification, directly recycle for the dissociation reaction in step (2)), first recover dichloromethane and 2-chloro-N,N-diethyl aniline from the organic phase under low vacuum, then distill the product 3-dichloromethyl-1H-methylpyrazole-4-butyrate 253.7 g under high vacuum, with a yield of 95.7%, gas phase detection: the content of 3-dichloromethyl-1H-methylpyrazole-4-butyrate is 99.628%, 5-dichloromethyl-1H-methylpyrazole-4-butyrate is not detected, and other impurities account for 0.372%.

[0071] Example 4 (1) Preparation of 3-dibutylaminopropyl acrylate Into a reaction flask, add xylene, cerium trichloride 6.5 g and aqueous solution of dibutylamine hydrochloride (containing dibutylamine hydrochloride 1657 g from the aqueous phase of the free step by-product), cool to below -10 ℃, add a xylene solution of sodium 3-hydroxypropyl acrylate (containing sodium 3-hydroxypropyl acrylate 1521 g), after adding, keep 0 ℃ for 6 hours, separate the layers, recover xylene from the organic phase by reduced pressure distillation for reuse, and then obtain 3-dibutylaminopropyl acrylate by high vacuum distillation, with a gas phase content of 99.57% and a yield of 96.2%.

[0072] (2) Condensation and free reaction Under nitrogen protection, add 3-dibutylaminopropyl acrylate 241.4 g and 980 g phenetol into a four-necked flask, cool to 20 ℃, load dichloroacetyl chloride 162.1 g and 3-nitro-N,N-dimethylaniline 191.1 g into two dropping funnels respectively, keep 20~25 ℃, and drop into the reaction flask at the same time, after dropping, keep 1 hour, during the reaction, solid gradually precipitates. After the reaction is completed, keep 25~35 ℃, add 45% aqueous solution of dibutylamine (containing dibutylamine 155.1 g) to the system, after adding, stir for 0.5 hours, at this time, there is no solid in the system, separate the layers, the aqueous phase mainly contains dibutylamine hydrochloride, which can be reused in step (1). Collect the basic co-solvent solution of 2-dichloroacetyl-3-(dibutylamino) propyl acrylate, which can be directly used for cyclization reaction without treatment.

[0073] (3) Preparation of 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid propyl ester Into a four-necked flask, add 40% methylhydrazine 430.1 g, benzyltrimethylammonium hydroxide 92.0 g, 1100 g phenetol, cool to -40 ℃, and cool the basic co-solvent solution (containing 2-dichloroacetyl-3-(dibutylamino) propyl acrylate 352.3 g, 3-nitro-N,N-dimethylaniline 191.1 g, and phenetol 980 g) to about -10 ℃.

[0074] The internal temperature was kept at -40 to -35 °C, the cooled basic cosolvent solution was added dropwise, and after the addition was completed, the reaction was kept stirring for 0.5 hours, and the reaction was completed. The layers were separated. The water phase was evaporated to remove the dibutylamine (absorbed with water, no need for purification, directly recycled for the free reaction in step (2)), and the organic phase was first recovered with low vacuum to recover the phenetole and 3-nitro-N,N-dimethylaniline, and then evaporated with high vacuum to evaporate the product 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid propyl ester 242.6 g, with a yield of 96.6%, gas phase detection: 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid propyl ester content was 99.553%, isomer 5-dichloromethyl-1H-methylpyrazole-4-carboxylic acid propyl ester was not detected, and other impurities accounted for 0.447%.

[0075] Example 5 (1) Preparation of 3-dimethylaminoacrylonitrile A reaction bottle was added with xylene, cerium trichloride 6.0 g and dimethylamine hydrochloride aqueous solution (containing dimethylamine hydrochloride 815 g from the water phase of the free step coproduction), cooled to below -10 °C, and 3-hydroxyacrylonitrile sodium salt xylene solution (containing 3-hydroxyacrylonitrile sodium salt 910.4 g) was added, and after the addition was completed, the reaction was kept at 0 °C for 5 hours, and the layers were separated. The organic phase was recovered by reduced pressure rectification to recover xylene for reuse, and then high vacuum distillation was performed to obtain 3-dimethylaminoacrylonitrile, with a gas phase content of 99.46% and a yield of 96.5%.

[0076] (2) Condensation and free reaction Under nitrogen protection, a four-necked flask was added with 3-dimethylaminoacrylonitrile 96.1 g and 700.0 g of toluene, and cooled to 0 °C. Dichloroacetyl chloride 154.7 g and N,N-dimethylaniline 130.0 g were respectively loaded into two dropping funnels, and kept at 0 to 5 °C, and then dropped into the reaction flask at the same time. After the dropping was completed, the reaction was kept for 1 hour, and during the reaction, solid gradually precipitated. After the reaction was completed, the system was kept at 10 to 20 °C, and 35% dimethylamine aqueous solution (containing dimethylamine 49.5 g) was added into the system, and after the addition was completed, the system was stirred for 0.5 hours. At this time, no solid existed in the system, the layers were separated, and the water phase mainly contained dimethylamine hydrochloride, which could be reused in step (1). The basic cosolvent solution of 2-dichloroacetyl-3-(dimethylamino)acrylonitrile was collected, and could be directly used for the cyclization reaction without treatment.

[0077] (3) Preparation of 3-dichloromethyl-1H-methylpyrazole-4-carbonitrile A four-necked flask was added with 45% methylhydrazine 358.3 g, sodium hydroxide 18 g, 800 g of toluene, and cooled to -30 °C. The basic cosolvent solution (containing 2-dichloroacetyl-3-(dimethylamino)acrylonitrile 207.1 g, N,N-dimethylaniline 130.0 g, toluene 700 g) was cooled to about -15 °C.

[0078] The internal temperature was kept at -30 to -25 °C, the cooled basic cosolvent solution was added dropwise, and after the addition was completed, the reaction was kept stirring for 0.5 hours. The reaction was ended, and the layers were separated. The dimethylamine in the water phase was evaporated (absorbed by water, and directly recycled for the free reaction of step (2) without purification), and the organic phase was first recovered with low vacuum to recover the toluene and N,N-dimethylaniline, and then evaporated with high vacuum to evaporate the product 3-dichloromethyl-1H-methylpyrazole-4-carbonitrile 182.8 g, with a yield of 96.2%. The liquid phase detection spectrum of the obtained product is shown in Figure 4 The content of 3-dichloromethyl-1H-methylpyrazole-4-carbonitrile was 99.526%, the isomer 5-dichloromethyl-1H-methylpyrazole-4-carbonitrile was not detected, and other impurities accounted for 0.474%. The nuclear magnetic hydrogen spectrum is shown in Figure 5 The 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 6.75 (s, 1H), 3.94 (s, 3H). Comparative Example 1: without adding the free reaction step (1) Preparation of 3-dimethylaminoacrylate The preparation method was the same as that of Example 1.

[0079] (2) Condensation reaction Under nitrogen protection, 3-dimethylaminoacrylate 143.2 g and 670 g of toluene were added to a four-necked flask, which was cooled to 0 °C. Dichloroacetyl chloride 154.7 g and N,N-dimethylaniline 133.3 g were respectively loaded into two dropping funnels, and were simultaneously added into the reaction flask while keeping the temperature at 0 to 5 °C. After the addition was completed, the reaction was kept for 1 hour. During the reaction, solid gradually precipitated, and the reaction system was a suspension after the reaction was completed.

[0080] (3) Preparation of 3-dichloromethyl-1H-methylpyrazole-4-carboxylate 40% Methylhydrazine 345.5 g, sodium hydroxide 56 g, and 720 g of toluene were added to a four-necked flask, which was cooled to -30 °C. The suspension (containing 2-dichloroacetyl-3- (dimethylamino) acrylate 254.1 g, N,N-dimethylaniline hydrochloride 173.5 g, and toluene 670 g) could only be cooled to about 20 °C due to the too thick system, and could not be cooled to a lower temperature. The internal temperature was kept at -30 to -25 °C, the suspension was added dropwise, and after the addition was completed, the reaction was kept stirring for 1.5 hours. The reaction was ended, and the layers were separated. The organic phase was first recovered with low vacuum to recover the toluene and N,N-dimethylaniline, and then evaporated with high vacuum to evaporate the product 3-dichloromethyl-1H-methylpyrazole-4-carboxylate and the isomer 5-dichloromethyl-1H-methylpyrazole-4-carboxylate, with a total yield of 213.8 g, and a yield of 90.2%. The gas chromatography detection data of the collected product are shown in Figure 6As shown, the content of 3-dichloromethyl-1H-methylpyrazole-4-ethyl formate is 90.587%, and the content of isomer 5-dichloromethyl-1H-methylpyrazole-4-ethyl formate is 8.96%.

[0081] The organic phase of the basic co-solvent solution obtained by the free reaction is a mixed solution of dichloroacetyl-3-(dialkylamino) acrylate, aryl tertiary amine and aprotic solvent 1, which is a homogeneous solution, and no solid is precipitated even when the temperature is lowered to-20℃, which is beneficial to uniform dropwise addition, control of reaction temperature and fast reaction speed. In the comparative example, it is a suspension, which is not conducive to uniform dropwise addition and lowering of temperature, and the reaction speed is slow, the reaction area selectivity is poor, and the yield is low.

[0082] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can modify the technical solutions described in the foregoing embodiments or make equivalent replacements to some technical features. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing compounds with improved purity of 3-dichloromethyl-1-substituted pyrazoles, characterized in that, Includes the following steps: In a water-insoluble aprotic solvent 1, using an organic nitrogen-containing weak base as an acid-binding agent, a condensation reaction is carried out between a 3-dialkylaminopropene compound and a dichloroacetyl halide to obtain a mixture of a 2-dichloroacetyl-3-(dialkylamino)propene compound and an organic nitrogen-containing weak base hydrohalide. A dialkylamine is added to the mixture to carry out a free reaction, and the mixture is separated into layers. An alkaline co-solvent solution of the 2-dichloroacetyl-3-(dialkylamino)propene compound is collected. The alkaline co-solvent solution of the 2-dichloroacetyl-3-(dialkylamino)propene compound is then added dropwise to a mixed solution of a hydrazine compound, a water-soluble base, and a water-insoluble aprotic solvent 2 to carry out a cyclization reaction to obtain a 3-dichloromethyl-1-substituted pyrazole compound.

2. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The method for preparing the 3-dialkylaminopropylene compounds is as follows: the sodium salt of 3-hydroxypropylene compounds reacts with an aqueous solution of dialkylamine hydrohalide salt to obtain the 3-dialkylaminopropylene compounds.

3. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 2, characterized in that, The structures of the 3-dialkylaminopropylene compounds are shown below. R1 and R2 are each independently selected from C1 to C4 alkyl groups; R3 is COOR4, CN; R4 is a C1 to C4 alkyl group.

4. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The water-insoluble aprotic solvent 1 and the water-insoluble aprotic solvent 2 are both at least one of aromatic hydrocarbons, halogenated aromatic hydrocarbons, alkanes, halogenated alkanes, cycloalkanes, ether solvents, ester solvents, and nitrile solvents.

5. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The organic nitrogen-containing weak base is one of, or a combination of at least two of, aromatic tertiary amine compounds, pyridine compounds, quinoline compounds, imidazole compounds, and pyrazine compounds, which have a pKa less than 7 and are insoluble in water.

6. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The mass ratio of the water-insoluble aprotic solvent 1, the water-insoluble aprotic solvent 2, and the organic nitrogen-containing weak base is 5~15:5~15:

1.

7. The method for preparing compounds with improved purity of 3-dichloromethyl-1-substituted pyrazoles according to claim 1, characterized in that, The molar ratio of the organic nitrogen-containing weak base, the 3-dialkylaminopropylene compound, and the dichloroacetyl halide is 1~4:1:1~2.

8. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The condensation reaction is carried out at a temperature of -30 to 60 °C.

9. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The structure of the dialkylamine is shown below: R1 and R2 are each independently selected from C1 to C4 alkyl groups; the dialkylamine is a 20% to 80% aqueous solution of dialkylamine.

10. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The molar ratio of the organic nitrogen-containing weak base to the dialkylamine is 1:1~4.

11. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The temperature for the free reaction is -30 to 80 ℃.

12. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The water-soluble alkali mentioned is an inorganic water-soluble alkali or an organic water-soluble alkali.

13. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The molar ratio of the water-soluble base to the 2-dichloroacetyl-3-(dialkylamino)propene compound is 0.1 to 1:

1.

14. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The alkaline co-solvent solution is first cooled to -40~20 ℃ and then added dropwise to a mixed solution of hydrazine compound, water-soluble base and water-insoluble aprotic solvent 2.

15. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The cyclization reaction is carried out at a temperature of -50 to 0 °C.

16. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The structure of the hydrazine compounds is shown below: R5 is selected from H, C1~C4 alkyl or cycloalkyl groups.

17. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The molar ratio of the hydrazine compound and the 2-dichloroacetyl-3-(dialkylamino)propene compound is 1~4:

1.

18. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The aqueous phase after the free reaction is an aqueous solution of dialkylamine hydrohalide, which is reused in the preparation of 3-dialkylaminopropylene compounds; the dialkylamine recovered after the cyclization reaction is reused in the free reaction.

19. The method for preparing 3-dichloromethyl-1-substituted pyrazole compounds according to claim 1, characterized in that, The yields of the condensation, freeing, and cyclization reactions reached over 95%.

20. The 3-dichloromethyl-1-substituted pyrazole compound prepared by any one of the preparation methods according to claims 1 to 19, wherein the purity of the 3-dichloromethyl-1-substituted pyrazole compound reaches 99% or more.

21. The 3-dichloromethyl-1-substituted pyrazole compound prepared by the method according to claim 1, wherein the structure of the 3-dichloromethyl-1-substituted pyrazole compound is as follows: in, R3 is COOR4 or CN; R4 is a C1-C4 alkyl group; R5 is selected from H, C1~C4 alkyl or cycloalkyl groups.

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