Preparation method of methyl 2, 6-dichloro-4-cyanobenzoate

Abstract

The invention belongs to the technical field of synthesis of ester compounds, and particularly relates to a preparation method of 2, 6-dichloro-4-cyanobenzoic acid methyl ester, which comprises the following steps: by taking dimethyl 2-aminoterephthalate as a raw material, sequentially carrying out substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction and dehydration reaction to obtain the 2, 6-dichloro-4-cyanobenzoic acid methyl ester. The 2, 6-dichloro-4-cyanobenzoic acid methyl ester is prepared by the method, and the yield reaches 59.28%. The N-chlorosuccinimide is used as a chlorine source to carry out substitution reaction on the 2-amino dimethyl terephthalate, so that the potential safety hazard caused by the traditional chlorination reagent is avoided, and the tert-butyl nitrite used in the deamination reaction avoids the potential safety hazard caused by the use of strong corrosive sulfuric acid; the amidation reaction is completed in one step by adopting a condensing agent, so that the complicated operation caused by firstly preparing acyl chloride and then carrying out condensation reaction is avoided, and therefore, the preparation method has the characteristics of safe preparation process, environment friendliness, simplicity in operation and the like under the condition of ensuring the product yield and purity.

Description

Technical Field

[0001] This application belongs to the technical field of ester compound synthesis. More specifically, it relates to a method for preparing methyl 2,6-dichloro-4-cyanobenzoate. Background Art

[0002] Methyl 2,6-dichloro-4-cyanobenzoate is a kind of ester compound, with its CAS number being: 409127-32-8; its English name being: methyl 2,6-dichloro-4-cyanobenzoate; and its chemical structural formula being Methyl 2,6-dichloro-4-cyanobenzoate contains multiple active functional groups such as chlorine atoms, cyano groups, and ester groups in its molecule. These functional groups make this compound exhibit high reactivity and diverse reaction paths in chemical reactions. In organic synthesis, it can either serve as a key intermediate, connecting reactants and target products through specific transformation steps, or as a starting material to initiate a series of complex chemical reaction routes to generate target molecules with specific functions or biological activities. This versatility makes methyl 2,6-dichloro-4-cyanobenzoate one of the highly potential compounds in the fields of drug research and development, pesticide creation, and high-performance material development.

[0003] The currently reported method for preparing methyl 2,6-dichloro-4-cyanobenzoate uses dimethyl 2-aminoterephthalate as the raw material and obtains methyl 2,6-dichloro-4-cyanobenzoate through substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction, and dehydration reaction in sequence. In this preparation method: Substitution reaction and deamination reaction: Using sulfonyl chloride as the chlorine source to conduct a substitution reaction on dimethyl 2-aminoterephthalate, and using concentrated sulfuric acid, acetic acid, etc. as solvents for the deamination reaction. Since sulfonyl chloride, concentrated sulfuric acid, etc. used in the preparation process are all highly dangerous and corrosive chemical reagents, these raw materials or reagents not only require extremely careful operation during use to prevent harm to operators, but also pose significant safety hazards and environmental pressure (not environmentally friendly) in their storage and waste treatment. Moreover, these raw materials or reagents require additional safety measures in the procurement, transportation, and storage links, resulting in an increase in the preparation cost; Amidation reaction: Completed in two steps. First, oxalyl chloride is used for oxalyl chloride chlorination reaction, and then the acyl chloride intermediate obtained from the oxalyl chloride chlorination reaction is used as the raw material and condensed with methylamine hydrochloride. At the same time, due to the harsh treatment conditions of the acyl chloride intermediate, an anhydrous environment needs to be strictly maintained. Therefore, the operation process of this amidation reaction is cumbersome and complex, not only increasing the time cost of the experiment, but also posing higher requirements for operators. Summary of the Invention

[0004] The object of the present application is to solve the technical problems such as insecurity, environmental unfriendliness, and complex operation process existing in the preparation method of methyl 2,6-dichloro-4-cyanobenzoate, and to provide a new preparation method of methyl 2,6-dichloro-4-cyanobenzoate. Under the condition of ensuring a comparable yield and purity to the prior art, this preparation method has higher safety and environmental friendliness, thus effectively reducing the risks and pollution in the production process. At the same time, this preparation method also has the characteristics of simple operation process.

[0005] The technical solution of the present application A preparation method of methyl 2,6-dichloro-4-cyanobenzoate, using dimethyl 2-aminoterephthalate as a raw material, and successively obtaining methyl 2,6-dichloro-4-cyanobenzoate through a substitution reaction, a deamination reaction, a hydrolysis reaction, an amidation reaction, and a dehydration reaction; for the said substitution reaction, using N-chlorosuccinimide and dimethyl 2-aminoterephthalate as raw materials, in a carbon tetrachloride solvent, controlling the temperature at 50-80 °C to carry out the substitution reaction, and the obtained reaction solution is filtered, extracted, and dried to obtain dimethyl 2-amino-3,5-dichloroterephthalate; For the said substitution reaction, the reaction process equation is as follows: By adopting the above technical solution, N-chlorosuccinimide is used as a raw material in the substitution reaction. Due to the relatively low toxicity of N-chlorosuccinimide and relatively stable reaction conditions, the potential safety risks are effectively reduced. At the same time, the high selectivity and stability of N-chlorosuccinimide in the reaction promote the effective generation of the target product and greatly reduce the generation of by-products. Therefore, using N-chlorosuccinimide as a raw material for the substitution reaction makes the substitution reaction process in the preparation method of methyl 2,6-dichloro-4-cyanobenzoate safe and controllable on the premise of ensuring a high yield of the intermediate dimethyl 2-amino-3,5-dichloroterephthalate.

[0006] Preferably, in the substitution reaction, the temperature of the substitution reaction process is 80 °C, and the dosages of dimethyl 2-aminoterephthalate, N-chlorosuccinimide, and carbon tetrachloride are in the ratio of dimethyl 2-aminoterephthalate:N-chlorosuccinimide:carbon tetrachloride of 1 mol:2-3 mol:1-2 L.

[0007] By adopting the above technical solution, the yield of the intermediate dimethyl 2-amino-3,5-dichloroterephthalate reaches 80.12-96.82%.

[0008] Further preferably, in the substitution reaction, the amounts of dimethyl 2-aminoterephthalate, N-chlorosuccinimide, and carbon tetrachloride are such that the ratio of dimethyl 2-aminoterephthalate:N-chlorosuccinimide:carbon tetrachloride is 1 mol:2.2 mol:1.67 L.

[0009] By adopting the above technical solution, the highest yield of the intermediate dimethyl 2-amino-3,5-dichloroterephthalate can reach 96.82%.

[0010] In the deamination reaction described above, using the intermediate dimethyl 2-amino-3,5-dichloroterephthalate obtained from the substitution reaction and tert-butyl nitrite as raw materials, the deamination reaction is carried out in a tetrahydrofuran solvent at a controlled temperature of 30 - 50 °C to obtain the intermediate dimethyl 3,5-dichloroterephthalate; For the deamination reaction described above, the reaction process equation is as follows:

[0011] By adopting the above technical solution, using tert-butyl nitrite as a raw material, this raw material has low requirements for use, and the process operations such as feeding are simple. At the same time, due to the use of tert-butyl nitrite, the reaction conditions for the deamination reaction are mild, enabling the deamination reaction to be completed without using strongly corrosive sulfuric acid, ensuring the safety of the deamination reaction process in the preparation method of methyl 2,6-dichloro-4-cyanobenzoate.

[0012] Preferably, in the deamination reaction described above, the temperature during the deamination reaction process is controlled at 50 °C, and the amounts of dimethyl 2-amino-3,5-dichloroterephthalate, tert-butyl nitrite, and tetrahydrofuran are such that the ratio of dimethyl 2-amino-3,5-dichloroterephthalate:tert-butyl nitrite:tetrahydrofuran is 1 mol:3 - 4 mol:1 - 2 L.

[0013] By adopting the above technical solution, the yield of the intermediate dimethyl 3,5-dichloroterephthalate can reach 56.26 - 85.40%.

[0014] Further preferably, in the deamination reaction described above, the amounts of dimethyl 2-amino-3,5-dichloroterephthalate, tert-butyl nitrite, and tetrahydrofuran are such that the ratio of dimethyl 2-amino-3,5-dichloroterephthalate:tert-butyl nitrite:tetrahydrofuran is 1 mol:3.2 mol:1.43 L.

[0015] By adopting the above technical solution, the highest yield of the obtained intermediate dimethyl 3,5-dichloroterephthalate can reach 85.40%.

[0016] For the hydrolysis reaction described above, using the intermediate dimethyl 3,5-dichloroterephthalate obtained from the deamination reaction as the raw material, an aqueous sodium hydroxide solution with a concentration of 0.6 - 0.8 M as the alkaline solution, and tetrahydrofuran as the solvent, the hydrolysis reaction is carried out at a controlled temperature of 25 - 50 °C to obtain the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid; For the hydrolysis reaction described above, the reaction process equation is as follows:

[0017] By adopting the above technical solution, hydrolyzing the intermediate dimethyl 3,5-dichloroterephthalate with an aqueous sodium hydroxide solution, the reaction conditions of this hydrolysis process are mild and controllable, thus avoiding the generation of by-products that may be brought about by violent reactions, improving the hydrolysis efficiency and the hydrolysis yield, laying a foundation for the subsequent separation and purification steps, and further ensuring the efficiency and economy of the entire production process. The yield of the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid in the hydrolysis reaction can reach 98.09%, and the purity can reach 94.26%.

[0018] For the amidation reaction described above: using the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid obtained from the hydrolysis reaction and isobutyl chloroformate as the raw materials, triethylamine (abbreviated as TEA) as the alkaline reagent, and tetrahydrofuran as the solvent, the amidation reaction is carried out at a controlled temperature of 0 - 30 °C; Or using the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid obtained from the deamination reaction as the raw material, reacting with 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (abbreviated as HATU) to undergo an intramolecular transfer to obtain the corresponding active ester, and then reacting with ammonium carbonate, using N,N-diisopropylethylamine (abbreviated as DIEA) as the base and N,N-dimethylformamide (abbreviated as DMF) as the solvent, the amidation reaction is carried out at a controlled temperature of 10 - 30 °C to obtain the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate; For the above two amidation reactions, the reaction process equations are as follows respectively:

[0019] By adopting the above technical solution, both of the two amidation reaction processes obtain the amidation product, that is, the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate, through only one-step reaction. Therefore, this amidation reaction has a simple preparation process and is convenient to operate.

[0020] Preferably, use 3,5-dichloro-4-(methoxycarbonyl)benzoic acid and isobutyl chloroformate as the raw materials to carry out the amidation reaction to prepare the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate.

[0021] With the above technical solution, using 3,5-dichloro-4-(methoxycarbonyl)benzoic acid and isobutyl chloroformate as raw materials, the yield is relatively higher. The possible reasons for this analysis are as follows: During the amidation reaction process with HATU as one of the raw materials, 3,5-dichloro-4-(methoxycarbonyl)benzoic acid will undergo side reactions with HATU during the reaction process, resulting in some by-products that are difficult to separate. The presence of these by-products not only reduces the purity of the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate but also affects its yield. At the same time, since HATU is a high-performance condensing agent, its price is relatively expensive, which will increase the cost of preparing the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate.

[0022] Further preferably, the temperature during the amidation reaction process is controlled at 25°C, and the amounts of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid, ammonium carbonate, isobutyl chloroformate, triethylamine, and tetrahydrofuran are in a volume ratio of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid: isobutyl chloroformate: ammonium carbonate: triethylamine: tetrahydrofuran of 1 mol: 1 - 2 mol: 2.5 - 3.5 mol: 1 - 2 mol: 1 - 2 L.

[0023] By adopting the above technical solution, the yield of the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate can reach 58.02 - 86.02%.

[0024] Even more preferably, for the amidation reaction, the amounts of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid, ammonium carbonate, isobutyl chloroformate, triethylamine, and tetrahydrofuran are in a volume ratio of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid: isobutyl chloroformate: ammonium carbonate: triethylamine: tetrahydrofuran of 1 mol: 1.1 mol: 3 mol: 1.1 mol: 1.53 L.

[0025] By adopting the above technical solution, the yield of the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate can reach 86.02%.

[0026] The dehydration reaction described above: The intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate obtained by amidation is subjected to a dehydration reaction in the presence of pyridine and trifluoroacetic anhydride, using dioxane as a solvent, and controlling the temperature at 10 - 30°C. Or, using the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate obtained by amidation as a raw material, in the presence of pyridine and trifluoroacetic anhydride, using dichloromethane as a solvent, and controlling the temperature at -10 - 20°C for a dehydration reaction to obtain the final product methyl 2,6-dichloro-4-cyanobenzoate. For the above two dehydration reactions, the reaction process equations are as follows:

[0027] By adopting the above technical solution, the preparation of methyl 2,6-dichloro-4-cyanobenzoate is successfully achieved.

[0028] Preferably, in the above dehydration reaction, dioxane is used as the solvent, and the reaction temperature is controlled at 25 °C during the dehydration reaction. The dosages of methyl 4-carbamoyl-2,6-dichlorobenzoate, pyridine, trifluoroacetic anhydride and the solvent dioxane are in the ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate:pyridine:trifluoroacetic anhydride:dioxane of 1 mol: 2.5 - 3.5 mol: 1.5 - 2.5 mol: 0.1 - 0.25 L.

[0029] By adopting the above technical solution, the yield of the final product methyl 2,6-dichloro-4-cyanobenzoate can reach 60.50 - 84.8%.

[0030] Further preferably, in the dehydration reaction, the dosages of methyl 4-carbamoyl-2,6-dichlorobenzoate, pyridine, trifluoroacetic anhydride, and dioxane are in the volume ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate:pyridine:trifluoroacetic anhydride:dioxane of 1 mol: 3 mol: 2 mol: 0.18 L.

[0031] By adopting the above technical solution, the yield of the final product methyl 2,6-dichloro-4-cyanobenzoate relative to the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate is the highest, which is 84.80%. Calculated based on dimethyl 2-aminoterephthalate as the benchmark, the yield of the final product methyl 2,6-dichloro-4-cyanobenzoate is 59.28%.

[0032] Preferably, in the preparation process of methyl 2,6-dichloro-4-cyanobenzoate, the reaction solutions obtained in each step of the substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction, dehydration reaction, etc. are purified through the following process: The reaction solution obtained from the substitution reaction is successively filtered, extracted, dried, and vacuum concentrated, and the purity of the intermediate dimethyl 2-amino-3,5-dichloroterephthalate obtained can reach 98.45%; The reaction solution obtained from the deamination reaction is successively concentrated and purified by a silica gel column, and the purity of the intermediate dimethyl 3,5-dichloroterephthalate obtained can reach 94.69%; The reaction solution obtained from the hydrolysis reaction is successively extracted, acidified, filtered, extracted, concentrated, and dried, and the purity of the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid obtained can reach 94.26%; The reaction solution obtained from the amidation reaction was successively subjected to pulping, filtration, and drying treatments, and the purity of the obtained intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate could reach 89.32%; The reaction solution obtained from the dehydration reaction was successively subjected to pulping, filtration, and drying treatments, and the purity of the obtained methyl 2,6-dichloro-4-cyanobenzoate reached 99.84%.

[0033] Advantageous technical effects of the present application: In the preparation method of methyl 2,6-dichloro-4-cyanobenzoate of the present application, since N-chlorosuccinimide is used as a specific chlorine source for the chlorination substitution of dimethyl 2-aminoterephthalate in the substitution reaction, and tert-butyl nitrite is used as a deamination reagent in the deamination reaction, the preparation process is simple, the operation is convenient, and the process is safe and controllable.

[0034] Furthermore, in the preparation method of methyl 2,6-dichloro-4-cyanobenzoate of the present application, due to the synergistic effects of the usage ratios of raw materials, auxiliary materials, and reagents, and the optimized process control parameters in each step of the substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction, dehydration reaction, etc., the products obtained in the corresponding steps finally all have relatively high yields. In particular, the yield of the final product methyl 2,6-dichloro-4-cyanobenzoate relative to the basic raw material dimethyl 2-aminoterephthalate can reach 59.28%.

[0035] Furthermore, in the preparation method of methyl 2,6-dichloro-4-cyanobenzoate of the present application, due to the optimized purification method for the reaction solutions obtained in each step of the substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction, dehydration reaction, etc., the highest purity of the final product methyl 2,6-dichloro-4-cyanobenzoate can reach 99.84%. Description of the Drawings

[0036] Figure 1a 、 1b 、1c is the LCMS data spectrum of the red viscous liquid obtained in step (1) of the substitution reaction of Example 1, that is, the intermediate dimethyl 2-amino-3,5-dichloroterephthalate; Figure 2a 、 2b 、2c is the LCMS data spectrum of the white solid obtained in step (2) of the deamination reaction of Example 1, that is, the intermediate dimethyl 3,5-dichloroterephthalate; Figure 3a 、 3b is the LCMS data spectrum of the white solid III obtained in step (3) of the hydrolysis reaction of Example 1, that is, the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid intermediate; Figure 4a 、4b 1. 4c is the LCMS data spectrum of the yellow solid, i.e., intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate, obtained from the amidation reaction in step (4) of Example 1; Figure 5 2. is the GCMS data spectrum of the white solid, i.e., the final product methyl 2,6-dichloro-4-cyanobenzoate, obtained from the dehydration reaction in step (5) of Example 1; Figure 6 3. is the 1H NMR spectrum of the white solid, i.e., the final product methyl 2,6-dichloro-4-cyanobenzoate, obtained from the dehydration reaction in step (5) of Example 1. Detailed Embodiments

[0037] The present application is further illustrated by specific examples in combination with the accompanying drawings, but does not limit the present application.

[0038] The raw materials, reagents, and solvents (except commercially available ones) required for preparation in each embodiment of the present application, the specific CAS numbers, purities, specifications, states, and manufacturer information are as follows: The equipment required for the detection and analysis of the intermediate products and final products in each embodiment of the present application, the specific detection parameters, manufacturer information, and models are as follows: The calculation formula for the yield of the intermediate or final product obtained in each step of the reaction in each embodiment = (actual mass of the intermediate or final product × purity) / theoretical mass of the intermediate or final product × 100%; The above-mentioned actual mass is the mass of each intermediate or final product obtained after purification of the reaction solution obtained in each step of the reaction in each embodiment of the present application; The above-mentioned theoretical mass is based on the raw materials used in each step of the reaction in each embodiment of the present application, and is the mass of each intermediate or final product that should theoretically be obtained after the reaction.

[0039] Example 1 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate, and the reaction equation in the preparation process is as follows: The specific steps in its preparation process are as follows: (1). Preparation of intermediate dimethyl 2-amino-3,5-dichloroterephthalate by substitution reaction Dimethyl 2-aminoterephthalate (300 g, 1434.028 mmol) was added to carbon tetrachloride (2.4 L) to obtain a suspension; Heat the above suspension to 60 °C, then add N-chlorosuccinimide (421.27 g, 3154.861 mmol) to the above suspension, and then heat it to 80 °C and stir for reaction for 16 h. The reaction process is monitored by LC-MS. At this time, the dimethyl 2-aminoterephthalate used in the preparation also just completely reacts, and reaction solution I is obtained; Filter the above-obtained reaction solution I under reduced pressure through a suction funnel with a 7-cm medium-speed qualitative filter paper. Wash the filter cake with dichloromethane (500 mL × 2), and mix the washed effluent and the filtrate obtained by suction filtration to obtain a mixed organic phase; Then extract the above-obtained mixed organic phase. The extraction process is to wash it successively with an aqueous sodium hydroxide solution (1 M, 1 L × 2), a saturated sodium sulfite solution (1 L × 2), deionized water (1 L × 2), and saturated brine (1 L × 2) to obtain the organic phase after extraction; Then the above-obtained organic phase after extraction is successively adsorbed by anhydrous sodium sulfate, filtered through qualitative filter paper, and concentrated at 42 °C under a vacuum of -90 KPa to obtain a red viscous oily liquid (390 g, 1588.424 mmol, yield 96.82% (calculation formula = (actual production amount of dimethyl 2-amino-3,5-dichloroterephthalate / theoretical production amount of dimethyl 2-amino-3,5-dichloroterephthalate) × 100%));

[0040] Perform LCMS testing on the above-obtained red viscous oily liquid. The obtained LCMS data spectrum is as Figure 1a 、 Figure 1b 、 Figure 1c shown. The peak emergence time is 2.752 min, the elution gradient is 5 - 95 (ACN / H2O), [M + H + + = 277.9, and the purity is 98.45%.

[0041] Through the above Figure 1a 、 1b LCMS data spectra shown in 1c, it can be concluded that the obtained red viscous oily liquid is dimethyl 2-amino-3,5-dichloroterephthalate, and the CAS number is 1258298-04-2; (2) Preparation of intermediate dimethyl 3,5-dichloroterephthalate by deamination reaction Add dimethyl 2-amino-3,5-dichloroterephthalate (390 g, 1402.449 mmol) to tetrahydrofuran (2000 mL) to obtain a mixed solution; ​At 0 °C, tert-butyl nitrite (462.79 g, 4487.836 mmol) was added dropwise to the above-obtained mixed solution. After the addition was completed, the mixture was heated to 50 °C, and the deamination reaction was carried out for 3 h under stirring. The reaction process was monitored by LCMS. At 3 h of the deamination reaction, the dimethyl 2-amino-3,5-dichloroterephthalate (390 g, 1402.449 mmol) used in the preparation was also completely reacted, and reaction solution II was obtained; The dropping rate of the above tert-butyl nitrite was 10 g / min; The above-obtained reaction solution II was cooled to 25 °C and then concentrated under vacuum. The obtained concentrated solution was purified by a silica gel column (quick separation column 40 - 63 μm 60A) (petroleum ether: ethyl acetate = 1:25), and a white solid (331 g, 1198.27 mmol) was obtained, with a yield of 85.40%; Yield = actual production amount of dimethyl 3,5-dichloroterephthalate (white solid) / theoretical production amount of dimethyl 3,5-dichloroterephthalate × 100%, where the theoretical production amount of dimethyl 3,5-dichloroterephthalate was calculated based on dimethyl 2-amino-3,5-dichloroterephthalate.

[0042] For the above-obtained white solid, LCMS test was carried out. The obtained LCMS data spectrum was as Figure 2a 、 Figure 2b 、 Figure 2c shown. The peak emergence time was 2.810 min, the elution gradient was 5 - 95 (ACN / H2O), [M + H + + = 262.9, and the purity was 94.69%; Through the above Figure 2a 、 Figure 2b 、 Figure 2c shown LCMS data spectrum, it can be concluded that the obtained white solid is dimethyl 3,5-dichloroterephthalate, and the CAS number is 264276 - 14 - 4; (3) Preparation of intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid by hydrolysis reaction Dimethyl 3,5-dichloroterephthalate (14 g, 53.218 mmol) was dissolved in tetrahydrofuran (80 mL) to obtain solution I; To the above-obtained solution I, an aqueous sodium hydroxide solution (2.24 g of sodium hydroxide, 55.879 mmol, 80 mL of water) was added and mixed evenly. Under stirring, the temperature was controlled at 25 °C for hydrolysis reaction for 16 h. The reaction process was detected by LC-MS. At this time, the dimethyl 3,5-dichloroterephthalate used in the preparation was also completely reacted, and reaction solution III was obtained; ​The obtained reaction solution III was rotary evaporated (at a temperature of 42 °C) to remove the organic solvent, obtaining an aqueous phase; The obtained aqueous phase was washed with EA (20 mL × 2) to remove impurities, then the pH was adjusted to 2 with dilute hydrochloric acid (1 - 3 M) for static precipitation. The obtained supernatant was filtered, and the obtained filter cake was completely dissolved in 500 mL of tetrahydrofuran and dried with anhydrous sodium sulfate, followed by vacuum filtration (qualitative filter paper). The obtained filtrate was concentrated at 42 °C under a vacuum of -90 KPa to obtain white solid I; To improve the yield of intermediate 3,5 - dichloro - 4 - (methoxycarbonyl) benzoic acid, the filtrate obtained from the above filtration was washed with EA (30 mL × 3), and then the organic phases were combined. Subsequently, they were rotary evaporated to dryness and dried (in the same process as the drying of the above filter cake) to obtain white solid II; White solid I and white solid II were mixed to obtain white solid III (13 g, 52.200 mmol), with a yield of 98.09%. The yield = (actual production amount of 3,5 - dichloro - 4 - (methoxycarbonyl) benzoic acid / theoretical production amount of 3,5 - dichloro - 4 - (methoxycarbonyl) benzoic acid) × 100%, where the theoretical production amount of 3,5 - dichloro - 4 - (methoxycarbonyl) benzoic acid was calculated based on dimethyl 3,5 - dichloroterephthalate); For the above - obtained white solid III, LCMS testing was performed. The obtained LCMS data spectrum is as shown in Figure 3a 、 3b shown. The peak elution time was 2.217 min, the elution gradient was 5 - 95 (ACN / H2O), [M - H - - = 246.9, and the purity was 94.26%.

[0043] From the above - mentioned Figure 3a 、 3b shown LCMS data spectrum, it can be concluded that the obtained white solid III is 3,5 - dichloro - 4 - (methoxycarbonyl) benzoic acid, with a CAS number of 264272 - 64 - 2; (4) Preparation of intermediate methyl 4 - carbamoyl - 2,6 - dichlorobenzoate by amidation reaction 3,5 - Dichloro - 4 - (methoxycarbonyl) benzoic acid (13 g, 52.200 mmol) and triethylamine (7.981 mL, 57.420 mmol) were successively added to tetrahydrofuran (80 mL) and then mixed evenly to obtain a mixed solution; ​Then, control the temperature of the mixed solution to 0 °C, and dropwise add isobutyl chloroformate (7.84 g, 57.420 mmol). After the addition is completed, continue to control the temperature at 0 °C and stir for 3 h. Then, filter to remove the filter residue. Add ammonium carbonate (15.05 g, 156.599 mmol) to the obtained filtrate, stir and mix well, and then control the temperature at 25 °C under stirring conditions for reaction for 16 h. The reaction process is detected by LC-MS. At this time, the dimethyl 3,5-dichloroterephthalate used in the preparation also just completely reacts, and reaction solution IV is obtained; The dropping rate of isobutyl chloroformate is 4 g / min; Add ethyl acetate (200 mL) and water (200 mL) to the above reaction solution IV, stir and mix well, and then let it stand for layer separation; after the obtained organic phase is rotary evaporated, add dichloromethane (20 mL) and petroleum ether (100 mL) in sequence, mix well, filter (qualitative filter paper) to collect the filter cake, and dry (drying temperature is 42 °C / vacuum degree is -90 kPa) to obtain a yellow solid (11.16 g, 44.99 mmol), with a yield of 86.2%. Yield = (actual production amount of methyl 4-carbamoyl-2,6-dichlorobenzoate / theoretical production amount of methyl 4-carbamoyl-2,6-dichlorobenzoate) × 100%, where the theoretical production amount of methyl 4-carbamoyl-2,6-dichlorobenzoate is calculated based on 3,5-dichloro-4-(methoxycarbonyl)benzoic acid); Perform LCMS testing on the above obtained yellow solid, and the obtained LCMS data spectrum is as Figure 4a 、 4b 、shown in 4c. The peak emergence time is 1.938 min, the elution gradient is 5 - 95 (ACN / H2O), [M - H+]+ = 247.9, and the purity is 89.32%; Through the Figure 4a 、 4b LCMS data spectrum shown in 4c, it can be concluded that the obtained yellow solid is methyl 4-carbamoyl-2,6-dichlorobenzoate, and the CAS number is 409127-31-7; (5) Preparation of intermediate methyl 2,6-dichloro-4-cyanobenzoate by dehydration reaction Dissolve methyl 4-carbamoyl-2,6-dichlorobenzoate (7 g, 28.219 mmol) in dioxane (5 mL), and sequentially add pyridine (6.847 mL, 84.657 mmol) and trifluoroacetic anhydride (15.773 mL, 56.438 mmol). Control the temperature at 25 °C and carry out dehydration reaction for 2 h under stirring conditions; the reaction process is detected by LC-MS. At this time, the intermediate dimethyl 3,5-dichloroterephthalate used in the preparation also just completely reacts, and reaction solution V is obtained; The above-mentioned trifluoroacetic anhydride (15.773 mL, 56.438 mmol) was added in two batches, with an addition amount of 7.887 mL each time, and the interval between the two batches of addition was 10 min; The reaction solution V obtained above was rotary evaporated (60 revolutions per minute, 42 °C, -95 KPa) to remove the organic solvent, then ethyl acetate (100 mL) and water (100 mL) were added, stirred and mixed evenly, and left to stand for liquid separation to obtain organic phase I; The obtained organic phase I was washed with 10% (mass percentage concentration) aqueous citric acid solution, stirred and mixed evenly, and left to stand for liquid separation to obtain organic phase II; After the organic phase II was rotary dried (-95 KPa), ethyl acetate (10 mL) and petroleum ether (80 mL) were added in sequence, mixed evenly, filtered (qualitative filter paper), and the filter cake was collected and dried (vacuum degree -100 KPa, temperature 35 °C) to obtain a white solid (5.5 g, 23.93 mmol, yield 84.80%, yield = actual production amount of methyl 2,6-dichloro-4-cyanobenzoate / theoretical production amount of methyl 2,6-dichloro-4-cyanobenzoate × 100%, where the theoretical production amount of methyl 4-carbamoyl-2,6-dichlorobenzoate was calculated based on methyl 4-carbamoyl-2,6-dichlorobenzoate); The white solid obtained from the dehydration reaction in the above step (5) was detected by gas chromatography-mass spectrometry, and the GCMS data spectrum of the obtained gas chromatography-mass spectrometry was as Figure 5 shown; The white solid obtained from the dehydration reaction in the above step (5) was measured by nuclear magnetic resonance hydrogen spectrum, and the data spectrum of the obtained nuclear magnetic resonance hydrogen spectrum was as Figure 6 shown, and the nuclear magnetic resonance hydrogen spectrum data was as follows: 1H NMR (400 MHz, dmso) δ 8.29 (s, 1H), 3.96 (s, 1H); Combined with the above Figure 5 , Figure 6 and the nuclear magnetic resonance hydrogen spectrum data, it can be concluded that the white solid obtained from the dehydration reaction in step (5) is methyl 2,6-dichloro-4-cyanobenzoate, with a purity of 99.84% and a CAS number of 409127-32-8.

[0044] During the preparation process of the above methyl 2,6-dichloro-4-cyanobenzoate, the raw materials, reagents, solvents used in each step, the dosage ratio relative to the raw materials, the reaction process temperature, the yield of the intermediate or final product obtained after each step of the reaction, and the purity of the intermediate or final product obtained after purification of the reaction solution obtained in each step are listed as follows: Examples 2 - 7 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate. Except that in the process of preparing intermediate dimethyl 2-amino-3,5-dichloroterephthalate by substitution reaction in step (1), the dosages of dimethyl 2-aminoterephthalate, N-chlorosuccinimide, and carbon tetrachloride used and the reaction temperature are different, the others are the same as in Example 1. Finally, a red oily viscous liquid is obtained, which is the intermediate dimethyl 2-amino-3,5-dichloroterephthalate; The dosages of dimethyl 2-aminoterephthalate, N-chlorosuccinimide, and carbon tetrachloride, the reaction temperature, and the yield of intermediate dimethyl 2-amino-3,5-dichloroterephthalate (relative to dimethyl 2-aminoterephthalate) used in the substitution reactions of the above Examples 1, 2-7 are specifically as follows in the table (for comparative analysis, the relevant data of Example 1 are also listed in the table): Note: For the reaction solutions obtained in each reaction step of the preparation process, the unreacted raw materials and auxiliary materials are finally removed by silica gel column purification and then the yield of the corresponding intermediate is measured; It can be seen from the above table that for the substitution reactions of Example 1, Example 2, and Example 3: When keeping the dosage ratio of raw material dimethyl 2-aminoterephthalate to solvent and the substitution reaction temperature (80 °C) the same, in Example 2, when dimethyl 2-aminoterephthalate (mol):N-chlorosuccinimide (mol) = 1:2, the raw material dimethyl 2-aminoterephthalate was not completely reacted. Therefore, the yield of intermediate dimethyl 2-amino-3,5-dichloroterephthalate was significantly lower than that of Example 1 (dimethyl 2-aminoterephthalate (mol):N-chlorosuccinimide (mol) = 1:2.2). When the dosage of N-chlorosuccinimide was increased in Example 3 (dimethyl 2-aminoterephthalate (mol):N-chlorosuccinimide (mol) = 1:3), the yield of intermediate dimethyl 2-amino-3,5-dichloroterephthalate did not change significantly. Considering both the yield of intermediate dimethyl 2-amino-3,5-dichloroterephthalate and the preparation cost (the increase in the dosage of N-chlorosuccinimide not only caused waste but also greatly increased the complexity and difficulty of the post-treatment process of the substitution reaction). Therefore, the dosage of dimethyl 2-aminoterephthalate (mol):N-chlorosuccinimide (mol) in the substitution reaction process is preferably 1:2.2; Substitution reactions of Example 1, Example 4, and Example 5: When keeping the dosage ratio of raw materials and the substitution reaction temperature (80 °C) the same, when the ratio of dimethyl 2-aminoterephthalate (mol) to carbon tetrachloride (L) is 1:1 and 1:2 in Examples 4 and 5, the yields are significantly lower than that of Example 1. The possible reason for analysis is that the addition amount of carbon tetrachloride is too small, resulting in insufficient dissolution of raw materials, so that the system is not fully mixed, and the yield is significantly reduced. While too much addition of carbon tetrachloride will lead to a lower concentration of the reaction system, thus reducing the chemical reaction rate. Therefore, the dosage ratio of dimethyl 2-aminoterephthalate (mol) to carbon tetrachloride (L) is preferably 1:1.67; Substitution reactions of Example 1, Example 6, and Example 7: When keeping the dosage ratios of raw materials to reagents and raw materials to solvents the same, when the substitution reaction temperatures of Examples 6 and 7 are 65 °C and 50 °C respectively, compared with the substitution reaction temperature of 80 °C in Example 1, the reaction yields are both reduced. Considering both the reaction yield and the operation safety comprehensively (when the substitution reaction temperature in Example 1 is 80 °C, it just reaches the boiling point of the used solvent carbon tetrachloride, with limited improvement and a significant increase in the risk factor), therefore, the substitution reaction temperature is preferably 80 °C.

[0045] Examples 8 - 13 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate. Except that in the process of the deamination reaction in step (2) to prepare the intermediate dimethyl 3,5-dichloroterephthalate: the dosages of 2-amino-3,5-dichloroterephthalic acid dimethyl ester, tert-butyl nitrite, and tetrahydrofuran and the reaction temperature are different, others are the same as in Example 1. Finally, a white solid is obtained, which is the intermediate dimethyl 3,5-dichloroterephthalate; The dosages of 2-amino-3,5-dichloroterephthalic acid dimethyl ester, tert-butyl nitrite, and tetrahydrofuran, the reaction temperature, and the yield of the intermediate dimethyl 3,5-dichloroterephthalate (relative to 2-amino-3,5-dichloroterephthalic acid dimethyl ester) in the deamination reaction of step (2) in the above Examples 1, 8 - 13 are specifically as follows in the table (for comparative analysis, the relevant data of Example 1 are also listed in the table): Remarks: For the reaction solutions obtained in each reaction step of the preparation process, the unreacted raw materials and auxiliary materials are finally removed by silica gel column purification and then the yields of the corresponding intermediates are measured; As can be seen from the above table, in the deamination reaction of step (2) in Examples 1, 8 and 9: when the ratio of the amounts of raw material to solvent (dimethyl 2-amino-3,5-dichloroterephthalate (mol): tetrahydrofuran (L) is 1:1.43) and the reaction temperature (50 °C) are the same, in Example 8 when dimethyl 2-amino-3,5-dichloroterephthalate (mol): tert-butyl nitrite (mol) = 1:3, dimethyl 2-aminoterephthalate did not react completely, and the yield was significantly lower than that of Example 1 (dimethyl 2-amino-3,5-dichloroterephthalate (mol): tert-butyl nitrite (mol) = 1:3.2). When the amount of tert-butyl nitrite was increased in Example 9 (dimethyl 2-amino-3,5-dichloroterephthalate (mol): tert-butyl nitrite (mol) = 1:4), the yield did not change significantly. Considering the comprehensive preparation cost and yield, the ratio of dimethyl 2-aminoterephthalate (mol): tert-butyl nitrite (mol) is preferably 1:3.2; The deamination reaction of step (2) in Examples 1, 10 and 11: when the ratio of the amount of raw material dimethyl 2-aminoterephthalate (mol): auxiliary material tert-butyl nitrite (mol) is 1:3.2 and the reaction temperature (50 °C) are the same, the yields of Example 10 (dimethyl 2-aminoterephthalate (mol): tetrahydrofuran (L) = 1:1) and Example 11 (dimethyl 2-aminoterephthalate (mol): tetrahydrofuran (L) = 1:2) are both significantly lower than that of Example 1. The reason may be that too little tetrahydrofuran was added, resulting in insufficient dissolution of the raw materials, so that the system was not fully mixed, while too much tetrahydrofuran was added, resulting in a lower concentration of the reaction system, thus reducing the chemical reaction rate. Therefore, the ratio of dimethyl 2-aminoterephthalate (mol): tetrahydrofuran (L) is preferably 1:1.43; The deamination reaction of step (2) in Examples 1, 12 and 13: when the ratio of the amount of raw material (dimethyl 2-aminoterephthalate (mol): auxiliary material tert-butyl nitrite (mol) is 1:3.2 and the ratio of dimethyl 2-amino-3,5-dichloroterephthalate (mol): solvent tetrahydrofuran (L) is 1:1.43 are both maintained, when the reaction temperatures of Examples 12 and 13 are 40 °C and 60 °C respectively, the yields are both lower than that of Example 1. Therefore, the temperature is preferably 50 °C.

[0046] Examples 14 - 23 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate. Except that in the process of step (4) amidation reaction for preparing the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate, the dosages of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid, isobutyl chloroformate, ammonium carbonate, triethylamine, and tetrahydrofuran used and the reaction temperature are different, the others are the same as those in Example 1, and finally a yellow solid, i.e., the intermediate dimethyl 3,5-dichloroterephthalate, is obtained. The dosage ratios of the raw material (3,5-dichloro-4-(methoxycarbonyl)benzoic acid), auxiliary materials (isobutyl chloroformate, ammonium carbonate, and triethylamine), and solvent (tetrahydrofuran), the reaction temperature, and the yield of the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate (relative to 3,5-dichloro-4-(methoxycarbonyl)benzoic acid) in the step (4) amidation reaction of the above Examples 1, 14 - 23 are specifically as follows in the table (for comparative analysis, the relevant data of Example 1 are also listed in the table): Note: For the reaction solutions obtained in each reaction step of the preparation process, the unreacted raw materials and auxiliary materials are finally removed by silica gel column purification and then the yields of the corresponding intermediates are measured. As can be seen from the above table, in the amidation reaction of step (4) in Examples 1 and Examples 14-19: while maintaining the same dosage ratio of raw material dimethyl 2-amino-3,5-dichloroterephthalate (mol) to solvent tetrahydrofuran (L) (1:1.53) and the same reaction temperature (25°C), in Example 14 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:1:3:1.1), 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol) did not react completely, and the yield was significantly lower than that of Example 1. In Example 15 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:2:3:1.1), the yield did not change significantly; in Example 16 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:1.1:2.5:1.1), 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol) did not react completely, and the yield was significantly lower than that of Example 1. In Example 17 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:1.1:3.5:1.1), the yield did not change significantly; in Example 18 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:1:2.5:1), 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol) did not react completely, and the yield was significantly lower than that of Example 1. In Example 19 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:1.1:3:2), the yield did not change significantly; In summary, when increasing the dosages of isobutyl chloroformate, ammonium carbonate, and triethylamine, the yield did not change significantly. At the same time, considering that excessive dosage of isobutyl chloroformate increases the experimental risk, and excessive dosage of ammonium carbonate makes the reaction system uneven (solid and insoluble in organic solvents), therefore, the dosage ratio of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) is preferably 1:1.1:3:1.1; In the amidation reaction of step (4) of Example 1, Example 20 and Example 21: When the dosage ratio of raw materials to auxiliary materials (dimethyl 2-amino-3,5-dichloroterephthalate (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) is 1:1.1:3:1.1) and the reaction temperature (25 °C) are the same, the yields of Example 20 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): solvent tetrahydrofuran (L) = 1:1) and Example 21 (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): tetrahydrofuran (L) = 1:2) are both lower than that of Example 1. The possible reason for the analysis is that, the possible reason for the analysis is that, the amount of tetrahydrofuran added is too small, resulting in insufficient dissolution of the raw materials, so that the system is not fully mixed, while the excessive amount of tetrahydrofuran added leads to a lower concentration of the reaction system, thus reducing the chemical reaction rate. Therefore, the dosage ratio of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): tetrahydrofuran (L) is preferably 1:53; In the amidation reaction of step (4) of Example 1, Example 22 and Example 23: While maintaining the same dosage ratio of raw materials and auxiliary materials (3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): isobutyl chloroformate (mol): ammonium carbonate (mol): triethylamine (mol) = 1:1.1:3:1.1) and the same dosage ratio of raw materials and solvent (dimethyl 2-amino-3,5-dichloroterephthalate (mol): tetrahydrofuran (L) = 1:1.53), in Example 22 when the reaction temperature is 0 °C, the raw material dimethyl 2-aminoterephthalate hardly reacts, and in Example 23 the reaction temperature is 40 °C, and the yield is slightly lower than that of Example 1. Therefore, the temperature of the amidation reaction is preferably 25 °C.

[0047] Examples 24 - 32 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate. Except that in the process of preparing methyl 2,6-dichloro-4-cyanobenzoate by dehydration reaction in step (5), the dosages of methyl 4-carbamoyl-2,6-dichlorobenzoate, pyridine, trifluoroacetic anhydride, and dioxane and the reaction temperature are different, others are the same as in Example 1, and finally a white solid, namely methyl 2,6-dichloro-4-cyanobenzoate, is obtained; For the dehydration reaction in step (5) of the above Examples 1, 24 - 28, the dosage ratio of raw materials (methyl 4-carbamoyl-2,6-dichlorobenzoate), auxiliary materials (pyridine, trifluoroacetic anhydride), solvent (dioxane), reaction temperature, and the yield of the final product methyl 2,6-dichloro-4-cyanobenzoate (relative to methyl 4-carbamoyl-2,6-dichlorobenzoate) are specifically as follows in the table (for comparative analysis, the relevant data of Example 1 are also listed in the table): Note: For the reaction solutions obtained in each reaction step of the preparation process, the unreacted raw materials and auxiliary materials are finally removed by silica gel column purification, and then the yield of the corresponding final product is measured. In the dehydration reaction of step (5) in Examples 1 and 24-27: when keeping the same dosage ratio of raw material to solvent (dosage ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate: dioxane (L) = 1:0.18) and reaction temperature (25 °C), when the dosage ratios of raw materials and auxiliary materials in Examples 24 and 26, namely, methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): pyridine (mol): trifluoroacetic anhydride (mol) are 1:3:1.5 and 1:3:2.5 respectively, methyl 4-carbamoyl-2,6-dichlorobenzoate is not completely reacted and the yield is significantly lower than that in Example 1. While when the dosage ratios of raw materials and auxiliary materials in Examples 25 and 27, namely, methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): pyridine (mol): trifluoroacetic anhydride (mol) are 1:3:2.5 and 1:3.5:2 respectively, the yield has no obvious change. At the same time, considering that excessive amounts of trifluoroacetic anhydride and pyridine not only cause waste but also greatly increase the complexity and difficulty of the post-treatment process. Therefore, the dosage of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (mol): methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): pyridine (mol): trifluoroacetic anhydride (mol) is preferably 1:3:2. In the dehydration reaction of Step (5) in Example 1, Example 28, and Example 29: While keeping the dosage ratios of the raw material (methyl 4-carbamoyl-2,6-dichlorobenzoate) and the auxiliary materials (pyridine, trifluoroacetic anhydride) the same (the dosage ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): pyridine (mol): trifluoroacetic anhydride (mol) = 1:3:2) and the reaction temperature (25 °C) the same, the yields of Example 28 (methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): solvent dioxane (L) = 1:0.1) and Example 29 (methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): solvent dioxane (L) = 1:0.25) are significantly lower than that of Example 1 (methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): solvent dioxane (L) = 1:0.18). The possible reason for the analysis is that when the amount of dioxane added is too small, the raw materials are not fully dissolved, resulting in the system not being fully mixed. When the amount of dioxane added is too much, the concentration of the reaction system is low, thereby reducing the chemical reaction rate. Therefore, the dosage ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): dioxane (L) is preferably 1:0.18; In the dehydration reaction of Step (5) in Example 1, Example 30 - 32: While keeping the dosage ratios of the raw material (methyl 4-carbamoyl-2,6-dichlorobenzoate) and the auxiliary materials (pyridine, trifluoroacetic anhydride) the same (the dosage ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): pyridine (mol): trifluoroacetic anhydride (mol) = 1:3:2) and the dosage ratio of the raw material to the reagent the same (methyl 4-carbamoyl-2,6-dichlorobenzoate (mol): solvent dioxane (L) = 1:0.18), in Example 32, when the reaction temperature is 0 °C, the raw material methyl 4-carbamoyl-2,6-dichlorobenzoate hardly reacts. The yields of Example 31 (10 °C), Example 1 (25 °C), and Example 30 (40 °C) increase with the increase of temperature. However, when the temperature of Example 30 is increased to 40 °C, the yield does not change significantly. Therefore, the reaction temperature in the dehydration reaction process of Step (5) is preferably 25 °C.

[0048] Example 33 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate, except that the preparation method of the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate in the amidation reaction process of Step (4) is different, and the others are the same as in Example 1, and finally a yellow solid methyl 4-carbamoyl-2,6-dichlorobenzoate is obtained; The preparation method of the above intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate is specifically as follows: Dissolve 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (78 g, 313.199 mmol) in N,N-dimethylformamide (750 mL), and then successively add HATU (166.73 g, 438.478 mmol), DIEA (272.783 mL, 1565.995 mmol) and ammonium carbonate (42.13 g, 438.478 mmol); stir at 25 °C for 16 h, and use LC-MS to detect the reaction process. Dimethyl 3,5-dichloroterephthalate also just completely reacted to obtain reaction solution VI; Add ethyl acetate (2500 mL) and water (2500 mL) to the above reaction solution VI, stir and mix well, then let it stand for liquid separation. The obtained organic phase is washed once with 1 L of water and once with saturated brine, and the obtained mixed organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum (42 °C, -95 KPa). The obtained concentrated solution is purified by a silica gel column (330 g), and the elution system is petroleum ether:ethyl acetate = 3:1 to 2:1 to obtain a yellow solid (43000 mg, 173.387 mmol, yield 55.12%). Compared with Example 1, the yield decreased by 36.06%.

[0049] The obtained yellow solid was identified as the same substance as the yellow solid obtained in step (4) of Example 1, that is, methyl 4-carbamoyl-2,6-dichlorobenzoate with CAS number 409127-31-7.

[0050] Example 34 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate, except that the dehydration reaction in step (5) for the preparation method of methyl 2,6-dichloro-4-cyanobenzoate is different, the others are the same as in Example 1, and finally white solid methyl 2,6-dichloro-4-cyanobenzoate is obtained; The above preparation method of methyl 2,6-dichloro-4-cyanobenzoate is specifically as follows: Dissolve methyl 4-carbamoyl-2,6-dichlorobenzoate (43 g, 173.346 mmol) in dichloromethane (430 mL), and then add pyridine (42.061 mL, 520.038 mmol) to obtain a mixed solution, Under the condition of a temperature of 0 °C and controlling the dropping rate at 2 g / min, drop trifluoroacetic anhydride (15.773 mL, 56.438 mmol) into the above mixed solution. After the dropping is completed, control the temperature at 25 °C and stir for 1 h for dehydration reaction. Use LC-MS to detect the reaction process. Dimethyl 3,5-dichloroterephthalate also just completely reacted to obtain reaction solution VI; The obtained reaction solution VI was cooled to 0 °C, 300 mL of water was added, and after stirring and mixing evenly, it was allowed to stand for liquid separation. The obtained organic phase was cooled to 0 °C, and 300 mL of saturated sodium bicarbonate aqueous solution was added dropwise with stirring for liquid-liquid extraction. The obtained organic phase was washed with saturated brine (200 mL×1), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum (42 °C, -95 KPa) to obtain a concentrated solution; Ethyl acetate (10 mL) and petroleum ether (100 mL) were added to the above concentrated solution and mixed evenly. The filter cake was collected by filtration and dried to obtain a white solid (30.00 g, 129.106 mmol, the yield was 74.48%, compared with step (5) of Example 1, the yield decreased by 12.22%); The obtained pale yellow solid was identified as the same substance as the white solid obtained in step (5) of Example 1, that is, methyl 2,6-dichloro-4-cyanobenzoate with CAS number 409127-32-8.

[0051] Examples 35-37 A preparation method of methyl 2,6-dichloro-4-cyanobenzoate. Except that during the dehydration reaction in step (5) to prepare methyl 2,6-dichloro-4-cyanobenzoate, the feeding method of trifluoroacetic anhydride (15.773 mL, 56.438 mmol) was different (in Examples 35, 36, and 37, it was added all at once, added in 3 batches (equal amount per batch, with an interval of 10 min), added in 4 batches (equal amount per batch, with an interval of 10 min)), other steps were the same as those in Example 1. Finally, white solid methyl 2,6-dichloro-4-cyanobenzoate was obtained, and the yields were 83%, 85%, and 85% respectively. Therefore, during the dehydration reaction in step (5) of a preparation method of methyl 2,6-dichloro-4-cyanobenzoate, trifluoroacetic anhydride is preferably added in 2-4 equal batches, and the interval between every two adjacent batches is 10 min.

[0052] In summary, a preparation method of methyl 2,6-dichloro-4-cyanobenzoate of the present application uses dimethyl 2-aminoterephthalate as the starting material, and through 5 steps of reactions, methyl 2,6-dichloro-4-cyanobenzoate is successfully prepared. The finally obtained methyl 2,6-dichloro-4-cyanobenzoate has a high yield and high purity. The highest yield can reach 59.28%, and the highest purity can reach 99.84%. While ensuring efficient synthesis, this preparation method also fully considers safety factors. Each step of the reaction is carried out under safe conditions, with simple operation and environmental friendliness, laying a solid foundation for future industrial production.

[0053] This specific embodiment is only an interpretation of the present application and does not limit the present application. After reading this specification, those skilled in the art can make modifications to this embodiment that do not contribute creatively as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A method for preparing methyl 2,6-dichloro-4-cyanobenzoate, which uses dimethyl 2-aminoterephthalate as a raw material and successively obtains methyl 2,6-dichloro-4-cyanobenzoate through substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction, and dehydration reaction, characterized in that, The substitution reaction: Using N-chlorosuccinimide and dimethyl 2-aminoterephthalate as raw materials, in carbon tetrachloride solvent, controlling the temperature at 50 - 80 °C to carry out the substitution reaction to obtain the intermediate dimethyl 2-amino-3,5-dichloroterephthalate.

2. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 1, characterized in that, In the described substitution reaction, the temperature during the substitution reaction process is controlled at 80 °C. The dosages of dimethyl 2-aminoterephthalate, N-chlorosuccinimide, and carbon tetrachloride are in the ratio of dimethyl 2-aminoterephthalate : N-chlorosuccinimide : carbon tetrachloride of 1 mol : 2 - 3 mol : 1 - 2 L.

3. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 2, characterized in that, In the described substitution reaction, the dosages of dimethyl 2-aminoterephthalate, N-chlorosuccinimide, and carbon tetrachloride are in the ratio of dimethyl 2-aminoterephthalate : N-chlorosuccinimide : carbon tetrachloride of 1 mol : 2.2 mol : 1.67 L.

4. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 3, characterized in that, The deamination reaction: Using dimethyl 2-amino-3,5-dichloroterephthalate and tert-butyl nitrite as raw materials, in tetrahydrofuran solvent, controlling the temperature at 40 - 60 °C to carry out the deamination reaction to obtain the intermediate dimethyl 3,5-dichloroterephthalate.

5. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 4, characterized in that, In the described deamination reaction, the temperature during the deamination reaction process is controlled at 50 °C. The dosages of dimethyl 2-amino-3,5-dichloroterephthalate, tert-butyl nitrite, and tetrahydrofuran are in the ratio of dimethyl 2-amino-3,5-dichloroterephthalate : tert-butyl nitrite : tetrahydrofuran of 1 mol : 3 - 4 mol : 1 - 2 L.

6. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 5, characterized in that, In the described deamination reaction, the dosages of dimethyl 2-amino-3,5-dichloroterephthalate, tert-butyl nitrite, and tetrahydrofuran are in the ratio of dimethyl 2-amino-3,5-dichloroterephthalate : tert-butyl nitrite : tetrahydrofuran of 1 mol : 3.2 mol : 1.43 L.

7. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 6, characterized in that, The amidation reaction: Using 3,5-dichloro-4-(methoxycarbonyl)benzoic acid and ammonium carbonate as raw materials, isobutyl chloroformate as the condensing agent, triethylamine as the basic reagent, and tetrahydrofuran as the solvent, controlling the temperature at 0 - 30 °C to carry out the amidation reaction to obtain the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate; Or using 3,5-dichloro-4-(methoxycarbonyl)benzoic acid and ammonium carbonate as raw materials, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate as the condensing agent, diisopropylethylamine as the basic reagent, and N,N-dimethylformamide as the solvent, controlling the temperature at 10 - 40 °C to carry out the amidation reaction to obtain the intermediate methyl 4-carbamoyl-2,6-dichlorobenzoate.

8. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 7, characterized in that, In the described amidation reaction, the temperature during the amidation reaction process is controlled at 25 °C: When isobutyl chloroformate is used as the condensing agent, the dosages of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid, ammonium carbonate, isobutyl chloroformate, triethylamine, and tetrahydrofuran are in the ratio of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid : isobutyl chloroformate : ammonium carbonate : triethylamine : tetrahydrofuran of 1 mol : 1 - 2 mol : 2.5 - 3.5 mol : 1 - 2 mol : 1 - 2 L.

9. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 8, characterized in that, The dosages of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid, ammonium carbonate, isobutyl chloroformate, triethylamine, and tetrahydrofuran are in the ratio of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid:isobutyl chloroformate:ammonium carbonate:triethylamine:tetrahydrofuran = 1 mol:1.1 mol:3 mol:1.1 mol:1.53 L.

10. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 9, characterized in that, In the dehydration reaction described above, using methyl 4-carbamoyl-2,6-dichlorobenzoate as the raw material, in the presence of pyridine and trifluoroacetic anhydride, with dioxane as the solvent, the dehydration reaction is carried out while controlling the temperature at 10 - 40 °C to obtain methyl 2,6-dichloro-4-cyanobenzoate. Or using methyl 4-carbamoyl-2,6-dichlorobenzoate as the raw material, in the presence of pyridine and trifluoroacetic anhydride, with dichloromethane as the solvent, the dehydration reaction is carried out while controlling the temperature at -10 - 20 °C to obtain methyl 2,6-dichloro-4-cyanobenzoate.

11. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 10, characterized in that, In the dehydration reaction described above, the temperature during the dehydration reaction process is controlled at 25 °C, with dioxane as the solvent. The dosages of methyl 4-carbamoyl-2,6-dichlorobenzoate, pyridine, trifluoroacetic anhydride, and dioxane are in the ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate:pyridine:trifluoroacetic anhydride:dioxane = 1 mol:2.5 - 3.5 mol:1.5 - 2.5 mol:0.1 - 0.25 L.

12. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 11, characterized in that, In the dehydration reaction described above, with dioxane as the solvent, the dosages of methyl 4-carbamoyl-2,6-dichlorobenzoate, pyridine, trifluoroacetic anhydride, and dioxane are in the volume ratio of methyl 4-carbamoyl-2,6-dichlorobenzoate:pyridine:trifluoroacetic anhydride:dioxane = 1 mol:3 mol:2 mol:0.18 L.

13. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 12, characterized in that, During the dehydration reaction process, trifluoroacetic anhydride is added in 2 - 4 equal batches, and the interval time between every two adjacent batches is 10 min.

14. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 13, characterized in that, The hydrolysis reaction described above: Using dimethyl 3,5-dichloroterephthalate as the raw material, with an aqueous sodium hydroxide solution as the alkaline solution, in a tetrahydrofuran solvent, the hydrolysis reaction is carried out while controlling the temperature at 10 - 30 °C to obtain the intermediate 3,5-dichloro-4-(methoxycarbonyl)benzoic acid.

15. The preparation method of methyl 2,6-dichloro-4-cyanobenzoate according to claim 1, characterized in that, The purification processes of the reaction solutions obtained from the substitution reaction, deamination reaction, hydrolysis reaction, amidation reaction, and dehydration reaction are as follows: The reaction solution obtained from the substitution reaction is successively subjected to filtration, extraction, drying, and vacuum concentration. The reaction solution obtained from the deamination reaction is successively subjected to concentration and silica gel column purification. The reaction solution obtained from the hydrolysis reaction is successively subjected to extraction, acid adjustment, filtration, extraction, concentration, and drying. The reaction solution obtained from the amidation reaction is successively subjected to slurrying, filtration, and drying. The reaction solution obtained from the dehydration reaction is successively subjected to slurrying, filtration, and drying.

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