Synthesis process of flubendiamide

Abstract

The invention relates to a synthesis process of chlorfenapyr flubendiamide, which comprises the following steps: in the presence of ionic liquid, reacting 2-fluoro-3-(N-methyl benzamide)-N-(2-(trifluoromethyl) phenyl) benzamide with 2-chloro heptafluoroisopropane to obtain 2-fluoro-3-(N-methyl benzamide)-N-(2-(trifluoromethyl) phenyl) benzamide; the preparation method comprises the following steps: preparing an intermediate 2-fluoro-3-(N-methyl benzamide)-N-(2-(trifluoromethyl)-4-heptafluoroisopropyl-phenyl) benzamide; the intermediate is subjected to a bromination reaction, the chlorfenapyr bisamide is prepared, and the ionic liquid disclosed by the invention is [HO3SC3NEt3] Cl-ZnCl2. According to the invention, heptafluoroisopropyl chloride is used as a raw material, is wide in source and low in price, is suitable for being used as an industrial raw material, can greatly reduce the production cost, can improve the reaction yield and the product purity, and is beneficial to industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis process of broflanilide. BACKGROUND

[0002] Broflanilide, English general name: Broflanilide, CAS registration number: 1207727-04-5. The original drug is white powder solid (20 DEG C), the melting point is 154.0 DEG C-155.5 DEG C, and it is easy to decompose above 180 DEG C. It is a product developed by Japan's Mitsubishi Chemical Corporation, and the company has signed an agreement with BASF, and both will jointly develop it, mainly for preventing and treating common pests on crops such as Lepidoptera, Coleoptera, termites and mosquitoes, and the current research shows that broflanilide has excellent activity on larvae and adults.

[0003] At present, there are few literatures on the synthesis of broflanilide at home and abroad, and the literatures mainly include the following methods: 1. The original drug is synthesized by taking 2-fluoro-3-(N-methyl benzamide) benzoic acid and 2-bromo-4-(perfluoro-propane-2-yl)-6-(trifluoromethyl) aniline as main intermediates:

[0004] This route is the most commonly used route for synthesizing broflanilide at present. The main product of the condensation of 2-fluoro-3-(N-methyl benzamide) benzoic acid and 2-bromo-4-(perfluoro-propane-2-yl)-6-(trifluoromethyl) aniline is an imide compound, and in order to obtain the original drug, the product needs to be subjected to multiple alkali decomposition with concomitant hot filtration. Moreover, the amount of 2-fluoro-3-(N-methyl benzamide) benzoic acid used in the reaction is 2.4 times that of the corresponding aniline, in order to avoid waste of raw materials, the acid needs to be recovered, and the whole process is not only complicated, but also needs a long reaction time.

[0005] 2. The original drug is synthesized by taking 2-fluoro-3-(N-methyl benzamide) benzoic acid and 2-bromo-6-iodo-4-(perfluoro-propane-2-yl) aniline as main intermediates:

[0006] This route takes 2-fluoro-3-(N-methyl benzamide) benzoic acid and 2-bromo-6-iodo-4-(perfluoro-propane-2-yl) aniline as main intermediates to construct the original drug core structure 1b 1 , and the condensation reaction involved in the route is easier to carry out than route 1 (without using catalyst 4-dimethylamino pyridine), but the complicated alkali decomposition and acid recovery operation also needs to be carried out, and 1b 1Afterwards, alkylation is required to finally obtain the active ingredient. The overall yield of the two-step synthesis is slightly lower than that of the one-step synthesis in Route 1.

[0007] 3. Synthesis of the active ingredient using 2-fluoro-3-(N-methylbenzamido)benzoic acid and 2-trifluoromethylaniline as the main intermediates:

[0008] This route yields the core structure 1b by condensation of 2-fluoro-3-(N-methylbenzoamido)benzoic acid with 2-trifluoromethylaniline. 2 The core structure reacts with 2-iodoheptafluoropropane, followed by bromination with N-bromosuccinimide (NBS) to obtain the technical grade. The heptafluoroisopropyl substitution reaction yields a slightly lower amount, and the remaining feedstock and product have similar properties, making product purification difficult. Furthermore, the bromination process is typically carried out in the presence of sodium hydride. In large-scale production, sodium hydride is not always easy to handle, and its transportation, storage, and handling requirements are quite stringent. If other inorganic bases, such as sodium hydroxide, are used, the yield is lower, and the overall yield of the route will decrease significantly.

[0009] 4. Synthesis of the active ingredient using 2-chloro-3-nitrobenzoic acid and 2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)aniline as the main intermediates:

[0010] This route uses 2-chloro-3-nitrobenzoic acid and 2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)aniline as the main intermediates to obtain the core structure 1b. 3 Then, fluorination was performed using KF, nitro reduction was performed using SnCl2, N-methylation was achieved via concentrated sulfuric acid-formaldehyde method, and finally, condensation with benzamide was performed to obtain the original drug. The core structure 1b... 3 The synthesis of this product requires the use of a strong base, lithium diisopropylamino (LDA), at -70°C. The reaction conditions are quite harsh, and the yield is also low. In the N-methyl step, concentrated sulfuric acid is used as both a catalyst and a solvent, which causes severe corrosion to the equipment. At the same time, each step of the reaction requires separation and purification using column chromatography.

[0011] 5. Synthesis of the active ingredient using 2-fluoro-3-nitrobenzoic acid and 2-bromo-6-iodo-4-(perfluoropropane-2-yl)aniline as the main intermediate:

[0012]

[0013] This route uses 2-fluoro-3-nitrobenzoic acid and 2-bromo-6-iodo-4-(perfluoropropane-2-yl)aniline as key intermediates to obtain the core structure 1b.4 which is alkylated with trifluoromethyltrimethylsilane, then reduced by nitro, N-methylated, and benzamidated to obtain the original drug. This route is similar to route 4, and the difference is that the reaction conditions for constructing the core structure are more mild, and the yield is more ideal, but the acid consumption is larger (2 times of aniline), and acid recovery is required. Each step of the reaction also needs to be purified and separated by column chromatography.

[0014] In view of the above defects in the prior art, the present inventors provide a synthesis process of broflanilide, which can greatly improve the yield of the reaction and the purity of the product, and the reaction conditions are mild, the price of the catalyst is cheap, the production cost can be significantly reduced, and it has good industrial application value. SUMMARY

[0015] The purpose of the present application is to provide a synthesis process of broflanilide to solve the technical problems of low reaction yield, harsh conditions and not conducive to industrialization in the prior art.

[0016] In a first aspect of the present application, a synthesis process of broflanilide is provided, which comprises the following steps: 1) 2-fluoro-3-(N-methylbenzamide)-N-(2-(trifluoromethyl)phenyl)benzamide shown in formula 1 reacts with 2-chloroheptafluoroisopropane in the presence of an ionic liquid to prepare 2-fluoro-3-(N-methylbenzamide)-N-(2-(trifluoromethyl)-4-heptafluoroisopropyl-phenyl)benzamide shown in formula 2; 2) bromination of the intermediate shown in formula 2 to prepare broflanilide; The reaction route is as follows:

[0017] wherein: wherein: the ionic liquid in step 1) is [HO3SC3NEt3]Cl-ZnCl2.

[0018] Preferably, the ionic liquid in step 1) is [HO3SC3NEt3]Cl-ZnCl2, wherein the molar fraction of ZnCl2 is 0.60-0.80; more preferably, the molar fraction of ZnCl2 is 0.65-0.75; most preferably, the molar fraction of ZnCl2 is 0.70.

[0019] Preferably, the molar ratio of the compound of formula 1 to 2-chloroheptafluoroisopropane is 1:1-1.5, more preferably 1:1.05-1.2.

[0020] Preferably, the mass ratio of 2-(3-(trifluoromethyl)phenyl)malonate shown in formula 1 to sulfonic acid-based imidazole type ionic liquid is 1:1-10.

[0021] Preferably, the reaction temperature of step 1) is 60-120°C, preferably 80-100°C.

[0022] Preferably, the reaction time of step 1) is 3-10 hours, more preferably 4-9 hours, most preferably 5-6 hours.

[0023] Preferably, after the completion of step 1), the following post-treatment step is further included: the reaction solution is cooled to 50°C, 200 mL of ethyl acetate is added for dilution, and the solution is washed with 5% NaHCO3 solution until neutral. The organic phase is dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude product; the crude product is recrystallized with a mixed solvent of ethanol and water to obtain the intermediate 2.

[0024] Preferably, the volume ratio of ethanol to water in the recrystallization solvent is 7:3.

[0025] Preferably, in step 2), NBS is used as the bromination reagent, and an oxidant is added to perform the bromination reaction.

[0026] Preferably, the oxidant of step 2) is benzoyl peroxide (BPO) or hydrogen peroxide.

[0027] In the prior art, when introducing a heptafluoroisopropyl group on a benzene ring, heptafluoroisopropyl iodine or heptafluoroisopropyl bromine is usually used as the raw material. The above-mentioned raw materials are expensive and difficult to source, and it is difficult to meet the requirements of industrial mass production. Heptafluoroisopropyl chloride is widely available and can be prepared by thermal chlorination of heptafluoropropane (HFC-227), and is low in price and suitable as an industrial raw material. However, compared with iodine and bromine, the leaving ability of chlorine is relatively weak, so that when heptafluoroisopropyl is used as the raw material, the reaction conditions are harsh, the yield is low, and thus the large-scale application is affected. For example, JP2003-335735A discloses that 2-methyl-4-heptafluoroisopropyl aniline is prepared using 2-methylaniline and heptafluoroisopropyl chloride as raw materials, and the reaction needs to be carried out under high pressure conditions and in the presence of sodium dithionite, and the yield is only 32%. However, the trifluoromethyl group of the raw material 2-fluoro-3-(N-methylbenzamide)-N-(2-(trifluoromethyl)phenyl)benzamide of the present application is a strong electron-withdrawing group, which reduces the electron cloud density on the benzene ring, and thus reduces the reactivity. If the method of JP2003-335735A is used, the yield will be even lower, or even no reaction will occur.

[0028] The process of introducing heptafluoroisopropyl on the benzene ring with heptafluoroisopropyl chloride as raw material can be regarded as Friedel-Crafts alkylation reaction. CN110776406A discloses a new Friedel-Crafts reaction catalyst SbF5, which can catalyze the reaction of heptafluoroisopropyl chloride and 2-nitrotoluene, and the yield is as high as 97% or more. However, a large amount of SbF5 is required in the reaction process, and high pressure reaction is required, which increases the production cost.

[0029] The Brønsted-Lewis dual acidic ionic liquid is a potential ionic liquid for catalyzing Friedel-Crafts alkylation reaction. The present application has screened the dual acidic ionic liquid of the present application as a reaction catalyst through a large amount of labor, greatly improved the yield of the reaction, reduced the production cost, and is more suitable for industrial production. At the same time, the ionic liquid has low volatility, and can be recycled and reused through simple separation (such as extraction, distillation); and the ionic liquid can replace traditional organic solvents and catalysts, reduce the emission of volatile organic compounds (VOCs); compared with traditional catalysts, the ionic liquid catalyst of the present application can reduce the reaction temperature and pressure, save energy.

[0030] The technical scheme of the present application has the following beneficial effects: 1) The heptafluoroisopropyl chloride used in the present application is widely available and low in price, and is suitable as an industrial raw material, which can greatly reduce the production cost.

[0031] 2) The method of the present application improves the yield and purity of the product, which is beneficial to industrial production.

[0032] 3) The ionic liquid used in the present application acts as a catalyst and a solvent for the reaction, and does not need to use other solvents, which saves the production cost. DETAILED DESCRIPTION

[0033] The specific embodiments will be described below to clearly and completely describe the technical scheme of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0034] Synthesis Example 1 Preparation of ionic liquid A series of ionic liquids [HO3SC3NEt3]Cl-ZnCl2 were synthesized according to the method reported by Zhang Kun et al. (Journal of Qingdao University of Science and Technology, 2022, 43(4): 14-19). The molar fraction of zinc chloride in ionic liquid A was 0.5 (i.e. [HO3SC3NEt3]Cl and ZnCl2 were in equimolar amount), the molar fraction of zinc chloride in ionic liquid B was 0.6, the molar fraction of zinc chloride in ionic liquid C was 0.7, and the molar fraction of zinc chloride in ionic liquid D was 0.8.

[0035] Example 1

[0036] Step 1): Into a dry reaction flask, a compound of formula 1 (41.6 g, 0.1 mol), ionic liquid C (50.0 g), and 2-chloroheptafluoroisopropane (22.4 g, 0.11 mol) were added. The reaction was stirred at 85-90°C under nitrogen protection for 5 hours (HPLC monitoring of raw material <1%). The reaction solution was cooled to 50°C, diluted with 200 mL of ethyl acetate, and washed with 5% NaHCO3 solution until neutral. The organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain a light yellow solid.

[0037] The crude product was recrystallized with ethanol / water (V:V=7:3) to obtain a white solid of compound of formula 2, 55.8 g, with a yield of 95.5% and an HPLC purity of 99.4%.

[0038] Step 2): The compound of formula 2 obtained in Example 1 (52.6 g, 0.09 mol) was dissolved in 150 mL of carbon tetrachloride, and N-bromosuccinimide (NBS) (17.8 g, 0.10 mol) and benzoyl peroxide (BPO) (0.6 g, 2.5 mmol) were added. The reaction was carried out at 80°C in the dark for 6 hours (TLC monitoring of end point). After cooling to room temperature, the succinimide was removed by filtration, and the filtrate was sequentially quenched with 10% Na2S2O3 solution (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was recrystallized with acetonitrile (120 mL) to obtain white needle-shaped crystals of bromoflumetofen (56.3 g), with a yield of 86.0% and an HPLC purity of 99.7%.

[0039] Example 2: Effect of different ionic liquids on the reaction The operation was the same as in Example 1, except that the molar fraction of ZnCl2 in the ionic liquid was changed, and the reaction results are shown below:

[0040] Example 3: Recycling of ionic liquid The washed aqueous phase of Example 1 was combined and the pH was adjusted to 2 with concentrated hydrochloric acid to precipitate the ionic liquid. The ionic liquid C was recovered after dehydration by distillation under reduced pressure. It was recycled for the alkylation reaction and the results are shown below:

[0041] Example 4 Step 1): Into a dry reaction flask was added the compound of Formula 1 (83.2 g, 0.2 mol), ionic liquid C (1000.0 g), 2-chloroheptafluoroisopropane (44.8 g, 0.22 mol). The reaction was stirred at 80-85 °C for 6 hours under nitrogen protection (HPLC monitoring of the starting material <1%). The reaction was cooled to 50 °C and diluted with 300 mL of ethyl acetate. The solution was washed with 5% NaHC03solution until neutral. The organic phase was dried over anhydrous MgS04and concentrated under reduced pressure to give a light yellow solid.

[0042] The crude product was recrystallized from ethanol / water (V:V=7:3) to give the compound of Formula 2 as a white solid, 54.2 g, yield 92.8%, HPLC purity 99.1%.

[0043] Comparative Example 1: No ionic liquid catalyst Without the ionic liquid, 25.0 g of zinc chloride was used as the catalyst and 50 mL of acetonitrile was used as the solvent. The other conditions were the same as in Example 1. After 24 hours, the starting material remained >98%, indicating that the reaction could not proceed without the ionic liquid catalyst of the present application.

Claims

1. A process for synthesizing brofentanil diamide, comprising the following steps: 1) In the presence of an ionic liquid, 2-fluoro-3-(N-methylbenzamide)-N-(2-(trifluoromethyl)phenyl)benzamide of Formula 1 reacts with 2-chloroheptafluoroisopropane to prepare 2-fluoro-3-(N-methylbenzamide)-N-(2-(trifluoromethyl)-4-heptafluoroisopropyl-phenyl)benzamide of Formula 2; 2) The intermediate shown in Formula 2 is subjected to a bromination reaction to obtain bromoxynil diamide; The reaction route is as follows: Among them: Among them: Step 1) The ionic liquid is [HO3SC3NEt3]Cl-ZnCl2.

2. The method according to claim 1, characterized in that, The mole fraction of ZnCl2 is 0.60~0.

80.

3. The method according to claim 2, characterized in that, The mole fraction of ZnCl2 is 0.

70.

4. The method according to any one of claims 1-3, characterized in that, The molar ratio of compound 1 to 2-chloroheptafluoroisopropane is 1:1~1.

5.

5. The method according to claim 1 or 2, characterized in that, The mass ratio of 2-(3-(trifluoromethyl)phenyl)malonate to sulfonic acid-imidazolium ionic liquid shown in Formula 1 is 1:1-10.

6. The method according to claim 1 or 2, characterized in that, The reaction temperature for step 1) is 60~120℃.

7. The method according to claim 1 or 2, characterized in that, The reaction temperature is 100~150℃, the reaction time is 2~6 h, and the reaction time for step 1) is 3~10 h.

8. The method according to claim 7, characterized in that, After the reaction in step 1) is completed, the following post-processing steps are also included: the reaction solution is cooled to 50°C, diluted with 200 mL of ethyl acetate, and washed with 5% NaHCO3 solution until neutral. The organic phase is dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain the crude product; the crude product is recrystallized from the crude product using a mixed solvent of ethanol and water to obtain intermediate 2.

9. The method according to claim 1 or 2, characterized in that, In step 2), NBS is used as the brominating agent, and an oxidizing agent is added to carry out the bromination reaction.

10. The method according to claim 9, characterized in that, The oxidizing agents in step 2) are benzoyl peroxide (BPO) and hydrogen peroxide.

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