阅读说明：本技术 一种合成3-氯-5-三氟甲基三氟苯乙酮的方法 (Method for synthesizing 3-chloro-5-trifluoromethyl trifluoro acetophenone ) 是由 赵云 闾肖波 陈鹏飞 刘陈阳 刘杰 于 2021-08-23 设计创作，主要内容包括：本发明公开了一种合成3-氯-5-三氟甲基三氟苯乙酮的方法,包括：邻氨基三氟甲苯先溴代再氯代,得到4-溴-2-氯-6-三氟甲基苯胺；4-溴-2-氯-6-三氟甲基苯胺经过重氮化后,用次磷酸或乙醇处理,得到脱氨基化合物1-溴-3-氯-5-(三氟甲基)苯；1-溴-3-氯-5-(三氟甲基)苯用镁屑做成格氏试剂,与酰化试剂发生亲核反应得到3-氯-5-三氟甲基三氟苯乙酮。该路线使用的起始原料邻氨基三氟甲苯为价格便宜的常见化学品,各步反应所得产物纯度好且收率都较高,对环境污染相对较小,有望用于规模化工业生产。(The invention discloses a method for synthesizing 3-chloro-5-trifluoromethyl trifluoro acetophenone, which comprises the following steps: o-amino benzotrifluoride is brominated and then chlorinated to obtain 4-bromo-2-chloro-6-trifluoromethylaniline; diazotizing 4-bromo-2-chloro-6-trifluoromethylaniline, and treating with hypophosphorous acid or ethanol to obtain deamination compound 1-bromo-3-chloro-5- (trifluoromethyl) benzene; preparing the 1-bromo-3-chloro-5- (trifluoromethyl) benzene into a Grignard reagent by using magnesium chips, and carrying out nucleophilic reaction with an acylation reagent to obtain the 3-chloro-5-trifluoromethyl trifluoroacetophenone. The o-amino benzotrifluoride used as the starting material in the route is a common chemical with low price, the product obtained by each step has good purity and higher yield, has relatively small environmental pollution, and is expected to be used for large-scale industrial production.)

1. A method for synthesizing 3-chloro-5-trifluoromethyl trifluoro acetophenone is characterized by comprising the following steps:

step S1: o-amino benzotrifluoride is brominated and then chlorinated to obtain 4-bromo-2-chloro-6-trifluoromethylaniline;

step S2: diazotizing 4-bromo-2-chloro-6-trifluoromethylaniline, and treating with hypophosphorous acid or ethanol to obtain deamination compound 1-bromo-3-chloro-5- (trifluoromethyl) benzene;

step S3: preparing the 1-bromo-3-chloro-5- (trifluoromethyl) benzene into a Grignard reagent by using magnesium chips, and carrying out nucleophilic reaction with an acylation reagent to obtain the 3-chloro-5-trifluoromethyl trifluoroacetophenone.

2. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 1, wherein step S1 comprises:

sequentially adding o-aminobenzotrifluoride, a first solvent and a first catalyst into a first reaction container, continuously stirring, controlling the internal temperature at 0-5 ℃, adding a bromization reagent, and preserving heat for 1-4 hours after the addition; naturally heating to the internal temperature of 25-30 ℃, and carrying out bromination reaction for 1-6 h under heat preservation; after the bromination reaction is finished, controlling the internal temperature at 25-30 ℃, adding a chlorination reagent into the bromination reaction, and preserving the temperature for chlorination reaction for 5-20 hours; after the chlorination reaction is finished, carrying out first post-treatment on the obtained first reaction liquid to obtain 4-bromo-2-chloro-6-trifluoromethylaniline;

the first solvent is at least one selected from dichloromethane, ethyl acetate, acetonitrile, N-hexane and N, N-dimethylformamide; the first catalyst is selected from one of sulfuric acid, methanesulfonic acid, aluminum trichloride, boron trifluoride, boron trichloride, ferric tribromide and iron powder; the brominating reagent is selected from one of bromine monochloride, N-bromosuccinimide and dibromohydantoin; the chlorinating agent is selected from one of trichloroisocyanuric acid, N-chlorosuccinimide and sulfonyl chloride;

wherein the mass ratio of the first solvent to the o-aminobenzotrifluoride is (2-10): 1, the molar ratio of the first catalyst to the o-aminobenzotrifluoride is (0.001-0.01): 1, the molar ratio of the effective bromine to the o-aminobenzotrifluoride in the brominating agent is (0.95-1.15): 1, the molar ratio of available chlorine to o-amino benzotrifluoride in the chlorination reagent is (0.95-1.15): 1.

3. the method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 2, wherein in step S1, the first post-treatment process is:

pouring the first reaction solution into ice water or water, stirring the first reaction solution in a first extraction solvent, standing the mixture for liquid separation, separating the obtained organic phase, washing the organic phase by using a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and finally performing rotary evaporation to obtain a first intermediate product, namely 4-bromo-2-chloro-6-trifluoromethylaniline.

4. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 3, wherein the first extraction solvent is dichloromethane, ethyl acetate or n-hexane.

5. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 1, wherein step S2 comprises:

adding the 4-bromo-2-chloro-6-trifluoromethylaniline prepared in the step S1 and water into a second reaction container in sequence, dropwise adding sulfuric acid into the second reaction container while continuously stirring, controlling the internal temperature to be 20-30 ℃, and preserving heat for 1-2 hours after dropwise adding; then, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution into the mixture, controlling the internal temperature to be 0-5 ℃, and after dropwise adding, carrying out heat preservation reaction for 1-2 hours to obtain a diazonium salt solution; adding a hypophosphorous acid aqueous solution into a third reaction container, continuously stirring, dropwise adding the diazonium salt solution into the third reaction container, controlling the internal temperature to be 20-30 ℃, keeping the temperature for 5-20 hours after the dropwise adding is finished, reacting for 5-20 hours to obtain a second reaction solution after the reaction is finished, and performing second post-treatment on the second reaction solution to obtain 1-bromo-3-chloro-5- (trifluoromethyl) benzene;

wherein the mass ratio of water to 4-bromo-2-chloro-6-trifluoromethylaniline is (3-5): 1; the molar ratio of the sulfuric acid to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-3): 1, the mass concentration of sulfuric acid is 80-98.3%; the molar ratio of the sodium nitrite to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-1.4): 1, the mass ratio of sodium nitrite to water in the sodium nitrite aqueous solution is (0.5-1): 1; the mass concentration of the hypophosphorous acid aqueous solution is 30-50%.

6. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 4, wherein in step S2, the second post-treatment process is:

adding dichloromethane into the second reaction solution, stirring, standing for liquid separation, separating to obtain an organic phase, washing the organic phase with a NaOH solution with the mass concentration of 1-20%, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, performing rotary evaporation to dryness, and performing reduced pressure rectification, wherein the top temperature is 85-86 ℃.

7. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 1, wherein step S2 comprises:

sequentially adding the 4-bromo-2-chloro-6-trifluoromethylaniline prepared in the step S1 and ethanol into a second reaction container, continuously stirring, dropwise adding sulfuric acid into the second reaction container, controlling the internal temperature to be 20-30 ℃, and preserving heat for 0.5-2 h after dropwise adding; adding NaNO to the second reaction vessel in batches at 20-30 DEG C₂Heating the solid to reflux after the solid is added, reacting for 4-7 h at the reflux temperature to obtain a second reaction solution, and performing second post-treatment to obtain 1-bromo-3-chloro-5- (trifluoromethyl) benzene;

wherein the mass ratio of the ethanol to the 4-bromo-2-chloro-6-trifluoromethylaniline is (3-5): 1; the molar ratio of the sulfuric acid to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-3): 1, the mass concentration of sulfuric acid is 80-98.3%; the molar ratio of the total amount of sodium nitrite to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-1.4): 1.

8. the method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 7, wherein in step S2, the second post-treatment process is:

and after carrying out rotary evaporation on the second reaction solution, adding water and methyl tert-butyl ether into a product obtained by rotary evaporation, stirring, standing for liquid separation, separating to obtain an organic phase, washing the organic phase with a saturated sodium chloride solution in sequence, drying with anhydrous sodium sulfate, filtering, carrying out rotary evaporation, and carrying out reduced pressure rectification, wherein the top temperature is 85-86 ℃.

9. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 1, wherein step S3 comprises:

under the protection of nitrogen, adding a second solvent, magnesium chips and an initiator into a fourth reaction vessel, adding a first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2 into the fourth reaction vessel, heating to 50-60 ℃, stopping heating after initiation, maintaining the internal temperature at 50-60 ℃ by utilizing the reaction heat release, after the reaction is finished, adding a second batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2 into the second reaction vessel in a dropwise manner, preserving the temperature for reaction for 1-3 hours after the dropwise addition is finished, and cooling to 15-25 ℃ after the reaction is finished to obtain a Grignard reagent solution; under the protection of nitrogen, continuously stirring, adding a third solvent and an acylating reagent into a fifth reaction container, controlling the internal temperature to be-85 to-55 ℃, then dripping the Grignard reagent solution into the fifth reaction container, controlling the internal temperature to be-80 to-60 ℃, and after finishing dripping, carrying out heat preservation reaction for 1 to 4 hours to obtain a third reaction solution; carrying out third post-treatment on the third reaction liquid to obtain 3-chloro-5-trifluoromethyl trifluoroacetophenone;

the second solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether, the initiator is iodine or/and 1, 2-dibromoethane, the third solvent is the same as the second solvent, and the acylating reagent is one of trifluoroacetyl chloride, trifluoroacetic anhydride and ethyl trifluoroacetate;

wherein the mass ratio of the second solvent to the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (3-9): 1, the mass ratio of the third solvent to the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-5): 1, the molar ratio of the magnesium chips to the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-1.5): 1, the molar ratio of the initiator to the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (0.001-0.01): 1, the molar ratio of the acylating reagent to 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-1.5): 1; the first amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is 1/30-1/10 of the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene, and the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is the sum of the first amount and the second amount.

10. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone of claim 9, wherein in step S3, the third post-treatment process is:

naturally heating the third reaction solution to an internal temperature of 10-20 ℃, dripping a dilute hydrochloric acid solution with a mass concentration of 5-10% into the third reaction solution, adding a third extraction solvent, stirring, standing for liquid separation, washing an organic phase obtained by separation with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, rotationally evaporating to dryness, and carrying out reduced pressure rectification to obtain a top temperature of 82-83 ℃; the third extraction solvent is methyl tert-butyl ether or 2-methyltetrahydrofuran.

Technical Field

The invention relates to a pesticide (such as pest repellent) intermediate containing fluorine, in particular to a synthetic method of fluorine-containing fine chemicals.

Background

Due to the unique property of fluorine element, fluorine-containing compounds have excellent performance and are more and more widely applied to the aspects of medicines, pesticides, materials and the like. However, our country has natural advantages in fluorine resources, and thus fluorine-containing fine chemicals as organic intermediates are gradually showing great growth potential.

Aforala (Afoxolaner), under the trade name nixin (NexGard), is the first oral anthelmintic for dogs to target both ticks and fleas in china marketed by blinge invargham in 2017 at 8 months. The compound belongs to an isoxazoline compound, and has the action principle that the nerve hyperexcitability is caused to die by inhibiting the GABA chloride channel of arthropods. At present, the number of Chinese pet dogs exceeds 6200 ten thousand. Canines are sexually active, are susceptible to various parasites, and may pose a hazard to both themselves and the health of the breeder, thus requiring a series of measures to kill the parasites. After the aforaline is taken for two hours, fleas are killed to cause the fleas to be incapable of laying eggs, the environmental pollution is avoided, the fleas can be effectively prevented from laying eggs for five weeks, 8 common cicadas can be killed, and the effect lasts for more than 1 month.

3-chloro-5-trifluoromethyl trifluoro acetophenone is an important intermediate for synthesizing alfilana, contains relatively active trifluoroacetyl group, and can also be used for synthesizing a plurality of pesticides.

The structural formula is shown as the following formula (I):

however, the synthesis of 3-chloro-5-trifluoromethyl trifluoroacetophenone is only rarely reported in the literature, and especially, a process route which has potential application to large-scale industrial production (e.g., low production cost) is not reported yet, and development and research are urgently needed.

Disclosure of Invention

In view of the above, the present invention is directed to a novel synthetic route and process for 3-chloro-5-trifluoromethyl trifluoroacetophenone, which can effectively reduce the cost by using a compound which is cheap and easily available as a starting material, and can perform a reaction using a relatively safe solvent while achieving a high reaction yield, thereby making it more likely to be used in industrial production.

The present invention contemplates the preparation of 3-chloro-5-trifluoromethyltrifluoroacetophenone by reaction of the corresponding organometallic reagent derived from 3-bromo-5-chlorotrifluoromethyltoluene of the following formula (II) with an acylating reagent.

However, the compound 3-bromo-5-chlorotrifluoromethylene of formula (II) is not a readily available compound and is expensive to market (chemical book shows 3-bromo-5-chlorotrifluoromethylene, 98% purity, 100g package, sold at 2120 yuan). This price is rather expensive, approaching or even exceeding the price of the product 3-chloro-5-trifluoromethyl trifluoroacetophenone, making the production cost of the route starting from 3-bromo-5-chlorotrifluoromethane very high, and obviously impossible to use in large-scale industrial production. Meanwhile, no report on the synthesis process of 3-bromo-5-chlorotrifluoromethylene exists in the current literature, so that the preparation thereof can be observed to have considerable technical difficulty. Based on the above facts, most studies have stopped exploring this synthetic route.

However, the present invention unexpectedly found a new synthetic route in repeated exploration: the 3-chloro-5-trifluoromethyl trifluoroacetophenone can be prepared at low cost by taking o-amino trifluorotoluene as a starting material through simple three-step treatment, the single-step yield can reach 97%, the purity of each intermediate product and the purity of a final product reach 98-99%, and the method is expected to be applied to large-scale industrial production.

Specifically, the invention adopts the following technical scheme to realize the purpose:

a method for synthesizing 3-chloro-5-trifluoromethyl trifluoro acetophenone comprises the following steps:

step S1: o-amino benzotrifluoride is brominated and then chlorinated to obtain 4-bromo-2-chloro-6-trifluoromethylaniline;

step S2: diazotizing 4-bromo-2-chloro-6-trifluoromethylaniline, and treating with hypophosphorous acid or ethanol to obtain deamination compound 1-bromo-3-chloro-5- (trifluoromethyl) benzene;

step S3: preparing the 1-bromo-3-chloro-5- (trifluoromethyl) benzene into a Grignard reagent by using magnesium chips, and carrying out nucleophilic reaction with an acylation reagent to obtain the 3-chloro-5-trifluoromethyl trifluoroacetophenone.

The above synthetic method can be represented by the following synthetic route:

in some embodiments, step S1 includes:

sequentially adding o-aminobenzotrifluoride, a first solvent and a first catalyst into a first reaction container, continuously stirring, controlling the internal temperature at 0-5 ℃, adding a bromization reagent, and preserving heat for 1-4 hours after the addition; naturally heating to the internal temperature of 25-30 ℃, and carrying out bromination reaction for 1-6 h under heat preservation; after the bromination reaction is finished, controlling the internal temperature at 25-30 ℃, adding a chlorination reagent into the bromination reaction, and preserving the temperature for chlorination reaction for 5-20 hours; after the chlorination reaction is finished, carrying out first post-treatment on the obtained first reaction liquid to obtain 4-bromo-2-chloro-6-trifluoromethylaniline;

the first solvent is at least one selected from dichloromethane, ethyl acetate, acetonitrile, N-hexane and DMF (N, N-dimethylformamide); the first catalyst is selected from one of sulfuric acid, methanesulfonic acid, aluminum trichloride, boron trifluoride, boron trichloride, ferric tribromide and iron powder; the brominating reagent is selected from one of bromine monochloride, NBS (N-bromosuccinimide) and dibromohydantoin; the chlorinating agent is selected from one of TCCA (trichloroisocyanuric acid), NCS (N-chlorosuccinimide) and sulfonyl chloride;

wherein the mass ratio of the first solvent to the o-aminobenzotrifluoride is (2-10): 1, the molar ratio of the first catalyst to the o-aminobenzotrifluoride is (0.001-0.01): 1, the molar ratio of the effective bromine to the o-aminobenzotrifluoride in the brominating agent is (0.95-1.15): 1, the molar ratio of available chlorine to o-amino benzotrifluoride in the chlorination reagent is (0.95-1.15): 1.

in some embodiments, in step S1, the brominating agent is added slowly, for example, dropwise or in multiple portions; the chlorinating agent is added slowly, for example, dropwise or in portions.

In some specific examples, in step S1, the first post-processing procedure is: pouring the first reaction solution into ice water or water, stirring the first reaction solution in a first extraction solvent, standing the mixture for liquid separation, separating the obtained organic phase, washing the organic phase by using a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and finally performing rotary evaporation to obtain a first intermediate product, namely 4-bromo-2-chloro-6-trifluoromethylaniline.

The first extraction solvent is dichloromethane, ethyl acetate or n-hexane. In some embodiments, when the first solvent is dichloromethane, ethyl acetate, or n-hexane, the first post-treatment may not require the addition of a first extraction solvent.

In certain embodiments, in step S1, the first reaction vessel is equipped with a tail gas absorber.

In some embodiments, step S2 includes:

adding the 4-bromo-2-chloro-6-trifluoromethylaniline prepared in the step S1 and water into a second reaction container in sequence, dropwise adding sulfuric acid into the second reaction container while continuously stirring, controlling the internal temperature to be 20-30 ℃, and preserving heat for 1-2 hours after dropwise adding; then, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution into the mixture, controlling the internal temperature to be 0-5 ℃, and after dropwise adding, carrying out heat preservation reaction for 1-2 hours to obtain a diazonium salt solution;

adding a hypophosphorous acid aqueous solution into a third reaction container, continuously stirring, dropwise adding the diazonium salt solution into the third reaction container, controlling the internal temperature to be 20-30 ℃, keeping the temperature for 5-20 hours after the dropwise adding is finished, obtaining a second reaction solution after the reaction is finished, and carrying out second post-treatment on the second reaction solution to obtain 1-bromo-3-chloro-5- (trifluoromethyl) benzene;

wherein the mass ratio of water to 4-bromo-2-chloro-6-trifluoromethylaniline is (3-5): 1; the molar ratio of the sulfuric acid to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-3): 1, the mass concentration of sulfuric acid is 80-98.3%; the molar ratio of the sodium nitrite to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-1.4): 1, the mass ratio of a solute (sodium nitrite) to a solvent (water) in a sodium nitrite aqueous solution is (0.5-1): 1; the mass concentration of the hypophosphorous acid aqueous solution is 30-50%.

In some embodiments, the mass concentration of sulfuric acid in step S2 is 98.3%.

In some embodiments, in step S2, the sulfuric acid is added in a slow dropwise manner. For example, in a specific embodiment, 246g of 98.3% concentrated sulfuric acid is added dropwise for 1 to 3 hours.

In some embodiments, in step S2, the concentration of the hypophosphorous acid aqueous solution is 50% by mass.

In some specific examples, in step S2, the second post-processing procedure is:

adding dichloromethane into the second reaction solution, stirring, standing for liquid separation, separating to obtain an organic phase, washing the organic phase with a NaOH solution with the mass concentration of 1-20%, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, performing rotary evaporation to dryness, performing reduced pressure rectification, and keeping the top temperature at 85-86 ℃.

In some embodiments, in step S2, the NaOH solution has a mass concentration of 3%.

Alternatively, step S2 may take another approach:

that is, in other embodiments, step S2 includes:

sequentially adding the 4-bromo-2-chloro-6-trifluoromethylaniline prepared in the step S1 and ethanol into a second reaction container, continuously stirring, dropwise adding sulfuric acid into the second reaction container, controlling the internal temperature to be 20-30 ℃, and preserving heat for 0.5-2 h after dropwise adding; adding NaNO to the second reaction vessel in batches at 20-30 DEG C₂Heating the solid to reflux after the solid is added, reacting for 4-7 h at the reflux temperature to obtain a second reaction solution, and performing second post-treatment to obtain 1-bromo-3-chloro-5- (trifluoromethyl) benzene;

wherein the mass ratio of the ethanol to the 4-bromo-2-chloro-6-trifluoromethylaniline is (3-5): 1; the molar ratio of the sulfuric acid to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-3): 1, the mass concentration of sulfuric acid is 80-98.3%; the molar ratio of the total amount of sodium nitrite to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-1.4): 1.

in step S2, NaNO is added in portions₂Solid, means several separate and single small charges, e.g., in one embodiment, 2g, 64g NaNO per charge₂The time taken for the addition of the solid was 2 h.

In some embodiments, in step S2, the sulfuric acid is added in a slow dropwise manner. For example, in a specific example, 72.9g of 98.3% concentrated sulfuric acid was added dropwise over 2 hours.

In some embodiments, the mass concentration of sulfuric acid in step S2 is 98.3%.

In some specific examples, in step S2, the second post-processing procedure is:

performing rotary evaporation on the second reaction liquid to recover most of ethanol; adding water and methyl tert-butyl ether into the rotary evaporated product, stirring, standing for liquid separation, separating to obtain an organic phase, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, finally, performing rotary evaporation to dryness, and performing reduced pressure rectification, wherein the top temperature is 85-86 ℃.

In some embodiments, step S3 includes:

under the protection of nitrogen, adding a second solvent, magnesium chips and an initiator into a fourth reaction vessel, adding a first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2 into the fourth reaction vessel, heating to 50-60 ℃, stopping heating after initiation, maintaining the internal temperature at 50-60 ℃ by utilizing the reaction heat release, after the reaction is finished, adding a second batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2 into the second reaction vessel in a dropwise manner, preserving the temperature for reaction for 1-3 hours after the dropwise addition is finished, and cooling to 15-25 ℃ after the reaction is finished to obtain a Grignard reagent solution;

under the protection of nitrogen, continuously stirring, adding a third solvent and an acylating reagent into a fifth reaction container, controlling the internal temperature to be-85 to-55 ℃, then dripping the Grignard reagent solution into the fifth reaction container, controlling the internal temperature to be-80 to-60 ℃, and after finishing dripping, carrying out heat preservation reaction for 1 to 4 hours to obtain a third reaction solution; carrying out third post-treatment on the third reaction liquid to obtain 3-chloro-5-trifluoromethyl trifluoroacetophenone;

the second solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether, the initiator is iodine or/and 1, 2-dibromoethane, the third solvent is the same as the second solvent, and the acylating reagent is one of trifluoroacetyl chloride, trifluoroacetic anhydride and ethyl trifluoroacetate;

wherein the mass ratio of the second solvent to the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (3-9): 1, the mass ratio of the third solvent to the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-5): 1, the molar ratio of the magnesium chips to the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-1.5): 1, the molar ratio of the initiator to the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (0.001-0.01): 1, the molar ratio of the acylating reagent to 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-1.5): 1; the first amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is 1/30-1/10 of the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene, and the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is the sum of the first amount and the second amount.

In some embodiments, in step S3, the first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is added dropwise rapidly and the second batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is added dropwise slowly.

In some embodiments, in step S3, the grignard reagent solution is added in a slow dropwise manner.

In some specific examples, in step S3, the third post-processing procedure is:

and naturally heating the third reaction solution to the internal temperature of 10-20 ℃, dripping a dilute hydrochloric acid solution with the mass concentration of 5-10% into the third reaction solution, adding a third extraction solvent, stirring, standing for liquid separation, washing an organic phase obtained by separation with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin-drying, carrying out reduced pressure rectification, and carrying out top temperature of 82-83 ℃.

In certain embodiments, the third extraction solvent is methyl tert-butyl ether or 2-methyltetrahydrofuran.

In some embodiments, the dilute hydrochloric acid solution has a mass concentration of 7%.

In the present invention, the internal temperature refers to the temperature of the solution in the reaction vessel.

In the present invention, the effective bromine in the brominating reagent refers to bromine element corresponding to bromide positive ion generated in the brominating reagent, and can also be referred to as oxidation state bromine contained in the brominating reagent.

In the present invention, the available chlorine in the chlorinating reagent refers to chlorine element corresponding to the generation of chlorine cations in the chlorinating reagent, and may be referred to as an oxidation state chlorine contained in the chlorinating reagent.

The invention also provides the 3-chloro-5-trifluoromethyl trifluoro acetophenone prepared by the synthesis method.

In the synthetic method, in the step S1, bromine and chlorine are skillfully added to the para position and the ortho position of amino respectively by utilizing an amino positioning effect, so that side reactions are effectively avoided, the purity of the synthesized 1-bromine-3-chlorine-5- (trifluoromethyl) benzene is more than 95 percent, the generation of two impurities, namely 1, 3-dichloro-5-trifluoromethylbenzene and 1, 3-dibromo-5-trifluoromethylbenzene, which have similar properties with an intermediate is effectively avoided, and the difficulty of post-treatment and purification is greatly reduced; in addition, bromination and chlorination are continuously carried out and can be finished in the same reaction container, and a brominated intermediate does not need to be separated, so that complicated steps of post-treatment can be reduced; in step S2, diazotization is used for direct deamination, and a complex process of firstly protecting amino and then deaminating is not needed; in the step S3, concentrated sulfuric acid is added dropwise to ensure the safety of the reaction, so that the low-temperature Grignard reaction is carried out under safe reaction conditions to prepare the 3-chloro-5-trifluoromethyl trifluoroacetophenone. The synthesis method takes the o-amino benzotrifluoride with wide sources and low cost as a reaction raw material, and the intermediate with the purity of 98-99% can be obtained to the maximum extent in each step of reaction, so that the total yield of the whole reaction is high, the purity of the final product is more 98%, the economic benefit is very obvious, the environmental pollution is low, and the synthesis method has potential application in large-scale industrial production.

Compared with the prior art, the invention has the following beneficial technical effects:

1. in the synthetic method, the steps of the whole route are few, only three times of post-treatment are needed, the post-treatment process of industrial production is simplified, the production time and the cost are greatly saved, the reaction mechanism is clear, the side reaction byproducts are few, the reaction condition is easy to regulate and control, the method is stable, the product yield is high, the product quality is stable, and the expanded production is convenient.

2. The method has the advantages of wide source of starting raw materials, easy obtainment, low price, capability of effectively reducing the production cost, high reaction yield of each step, accordance with the atom economy principle and potential application in large-scale industrial production.

3. The method has mild reaction conditions, does not have the conditions of high temperature and high pressure, reduces the treatment burden of the waste water and the waste liquid through acid-base neutralization, can reduce the production treatment cost and reduce the environmental pollution, and is suitable for industrial production.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of the product obtained in step (one) of example 1, which was identified as 4-bromo-2-chloro-6-trifluoromethylaniline.

FIG. 2 is a nuclear magnetic hydrogen spectrum of the product obtained in step (II) of example 1, which was identified as 1-bromo-3-chloro-5- (trifluoromethyl) benzene.

FIG. 3 is a nuclear magnetic hydrogen spectrum of the product obtained in step (III) of example 1, which was identified as that of 3-chloro-5-trifluoromethyltrifluoroacetophenone.

Detailed Description

In order to better explain the present invention and to facilitate the understanding of the technical solutions of the present invention, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the following examples are illustrative only and do not represent or limit the scope of the present invention, which is defined by the claims.

The reagents and instruments used in the following examples are not indicated by manufacturers, and are all conventional products available on the market. In the present invention, the raw materials used are all commercially available products. Among them, o-aminobenzotrifluoride is available at a price of about 6 ten thousand yuan/ton.

In the following examples, the gas phase monitoring of the reaction process refers to gas phase monitoring of the remaining amount of the reaction raw material, and is achieved by monitoring the value of the raw material peak integral area/(raw material peak integral area + product peak integral area) on the GC spectrogram. When the value is monitored to be < 0.5%, it means that the remaining amount of the reaction raw material is < 0.5%, and it can be regarded that the reaction has been completed.

Example 1

Synthesis of (I) 4-bromo-2-chloro-6-trifluoromethylaniline

200g of o-aminobenzotrifluoride (1eq), 1kg of dichloromethane and 0.1g of iron powder are sequentially added into a 2L three-necked bottle with a tail gas absorption device; starting stirring, cooling to 0 ℃, dropwise adding 144.7g of cold (about-15 ℃) bromine monochloride (1.01eq) into a three-necked bottle, controlling the internal temperature at 0-5 ℃, and preserving heat for 2 hours after dropwise adding is finished for 1-3 hours; then, naturally raising the temperature to 25 ℃, preserving the temperature to carry out bromination reaction, monitoring the reaction process of the raw material o-aminobenzotrifluoride in the bromination reaction by gas phase, and monitoring to show that: and (4) carrying out bromination reaction for 2h, and finishing the reaction of the raw material o-aminobenzotrifluoride.

After the o-amino benzotrifluoride reaction is finished, 169.2g of sulfonyl chloride (1.01eq) is dripped into the reaction liquid at 25 ℃, the internal temperature is controlled to be 25-30 ℃, the chlorination reaction is carried out after 1-3 h of dripping is finished, the reaction process of the 4-bromo-2-trifluoromethylaniline serving as the raw material in the chlorination reaction is monitored in a gas phase, and monitoring shows that: the chlorination reaction is carried out for 12h, and the reaction of the raw material 4-bromo-2-trifluoromethylaniline is finished.

After the reaction of 4-bromo-2-trifluoromethylaniline, the first reaction solution obtained was poured into 1kg of ice water, stirred, allowed to stand for liquid separation, and the organic phase obtained by separation was sequentially treated with 500g of saturated NaHCO₃The solution was washed once with 500g of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to obtain 337g of oily liquid.

The obtained oily liquid was subjected to Gas Chromatography (GC) and Hydrogen Nuclear Magnetic Resonance (HNMR) detection to determine its structural formula and purity. The NMR spectrum is shown in fig. 1, where in fig. 1, 1H NMR (400 MHz; DMSO-d6) δ is 7.74(d, J is 1.6Hz,1H),7.48(d, J is 2.4Hz,1H),5.90(s, 2H). From the analysis of FIG. 1, it was confirmed that the obtained oily liquid was 4-bromo-2-chloro-6-trifluoromethylaniline. The purity was 98% by GC and the calculated yield was 97%.

Synthesis of (di) 1-bromo-3-chloro-5- (trifluoromethyl) benzene

337g of 4-bromo-2-chloro-6-trifluoromethylaniline (1eq) and 1.35kg of water were added in this order to a 5L three-necked flask, and stirring was started. At room temperature (20-30 ℃), slowly dripping 246g of concentrated sulfuric acid (2eq) with the mass fraction of 98.3%, controlling the internal temperature at 20-30 ℃, and preserving heat for 1h after dripping is finished for 1-3 h. Then, the temperature is reduced to 0 ℃, and NaNO is dripped₂Aqueous solution (93.2g NaNO)₂Dissolving in 93.2g of water) (1.1eq), controlling the internal temperature at 0-5 ℃, keeping the temperature for 1-4 h, and then carrying out heat preservation reaction for 1h, wherein the reaction solution is detected to have oxidability by starch potassium iodide test paper, which indicates that the reaction solution is prepared into a diazonium salt aqueous solution.

Adding 486g of hypophosphorous acid aqueous solution (3eq) with the mass concentration of 50% into the other three-necked bottle with the volume of 5L, starting stirring, dropwise adding the diazonium salt aqueous solution at room temperature (20-30 ℃), controlling the internal temperature at 20-30 ℃, and after dropwise adding is finished for 2-4 h, keeping the temperature and reacting for 12h to obtain a second reaction solution.

Adding 1.3kg of dichloromethane into the second reaction solution, stirring, standing for liquid separation, washing the separated organic phase once with 500g of NaOH solution with the mass concentration of 3%, washing once with 1kg of saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, performing rotary evaporation, and finally performing reduced pressure rectification with a water pump at the top temperature of 85-86 ℃ to obtain 226g of colorless liquid.

The colorless liquid obtained was subjected to Gas Chromatography (GC) and Hydrogen Nuclear Magnetic Resonance (HNMR) detection to determine its structural formula and purity. The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 2, in which 1H NMR (400 MHz; CDCl) is shown in FIG. 2₃) δ is 7.70(s,1H),7.66(s,1H),7.56(s, 1H). From the analysis of FIG. 2, it was confirmed that the obtained colorless liquid was 1-bromo-3-chloro-5- (trifluoromethyl) benzene. The purity was 99% by GC and the calculated yield was 71%.

Synthesis of (tri) 3-chloro-5-trifluoromethyl trifluoro acetophenone

Under the protection of nitrogen, 1kg of 2-methyltetrahydrofuran, 24.6g of magnesium chips (1.16eq) and 1g of 1, 2-dibromoethane are added into a 3L three-necked bottle, 22.6g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.1eq, total 1eq) is added into the three-necked bottle, the heating is stopped after the initiation, the internal temperature is maintained at 50-60 ℃ by utilizing the reaction heat release, after the reaction of the raw materials in the bottle is finished, the residual 203.4g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.9eq, total 1eq) is slowly added dropwise, the reaction is kept warm after 1-3 h of dropwise addition is finished, the reaction process of the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is monitored in a gas phase, and the monitoring shows that: the reaction is carried out for 2h, and after the 1-bromo-3-chloro-5- (trifluoromethyl) benzene reaction is finished, the reaction solution is cooled to 20 ℃ at the moment, so that the Grignard reagent solution is obtained.

Under the protection of nitrogen, under the continuous stirring, adding 500g of 2-methyltetrahydrofuran into another 3L three-necked bottle, cooling to the internal temperature of-80 ℃ and keeping, then introducing 127g of trifluoroacetyl chloride gas (1.1eq), then slowly dropwise adding the Grignard reagent solution into the three-necked bottle, controlling the internal temperature to be-80 ℃ to-70 ℃, and after dropwise adding is completed for 1-2 hours, keeping the temperature and reacting for 2 hours to obtain a third reaction solution.

And naturally heating the third reaction liquid to 20 ℃, dropwise adding 1kg of a 7% dilute hydrochloric acid solution into the third reaction liquid, wherein the dropwise adding takes 20min, adding 300g of methyl tert-butyl ether, stirring, standing for liquid separation, washing an organic phase obtained by separation once with 500g of a saturated sodium chloride solution, drying and spin-drying with anhydrous sodium sulfate, and finally performing reduced pressure distillation with a water pump, wherein the top temperature is 82-83 ℃, so that 180g of colorless liquid is obtained.

The colorless liquid obtained was subjected to Gas Chromatography (GC) and Hydrogen Nuclear Magnetic Resonance (HNMR) detection to determine its structural formula and purity. The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 3, in which 1H NMR (400 MHz; CDCl) is shown in FIG. 3₃) δ -8.21-8.19 (m,2H),7.95(s, 1H). From the analysis of fig. 3, it was confirmed that the obtained colorless liquid was 3-chloro-5-trifluoromethyl trifluoroacetophenone, and the purity by GC was 99%, and the calculated yield was 75%.

Example 2

Synthesis of (I) 4-bromo-2-chloro-6-trifluoromethylaniline

120g of o-aminobenzotrifluoride (1eq), 800g of acetonitrile and 0.1g of aluminum trichloride were successively charged into a 2L three-necked flask, and stirring was started.

Cooling to 0 ℃, adding 117.1g of dibromohydantoin solid (0.55eq) in batches (3 g each time, 2 hours for feeding), controlling the internal temperature at 0-5 ℃, and preserving the temperature for 4 hours after the addition; naturally heating to 25 ℃, preserving the temperature to carry out bromination reaction, monitoring the reaction process of the raw material o-aminobenzotrifluoride in the bromination reaction by gas phase, and monitoring to show that: and (5) carrying out bromination reaction for 5h, and finishing the reaction of the raw material o-aminobenzotrifluoride.

After the o-amino benzotrifluoride reaction is finished, continuously adding 64g of TCCA solid (0.37eq) into the reaction liquid in batches (1 g each time, 3h for feeding) at 25 ℃, controlling the internal temperature to be 25-30 ℃, preserving the heat after the addition to carry out the chlorination reaction, monitoring the reaction process of the raw material 4-bromo-2-trifluoromethylaniline in the chlorination reaction in a gas phase, and monitoring and displaying: the chlorination reaction is carried out for 16h, and the reaction of the raw material 4-bromo-2-trifluoromethylaniline is finished.

After the reaction of 4-bromo-2-trifluoromethylaniline, the first reaction solution was poured into 1kg of water, and then 500g of ethyl acetate was added thereto, followed by stirring, standing for liquid separation, and separation of the organic phase obtained by the reaction in turn with 500g of saturated NaHCO₃The solution was washed once with 500g of saturated sodium chloride solution three times, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to obtain 200g of oily liquid.

The obtained oily liquid was subjected to Gas Chromatography (GC) and Hydrogen Nuclear Magnetic Resonance (HNMR) detection to determine its structural formula and purity. The oily liquid obtained was determined to be 4-bromo-2-chloro-6-trifluoromethylaniline by HNMR, and the purity was 98% by GC, with a calculated yield of 96%.

Synthesis of (di) 1-bromo-3-chloro-5- (trifluoromethyl) benzene

200g of 4-bromo-2-chloro-6-trifluoromethylaniline (1eq) and 800g of ethanol were added in succession to a 3L three-necked flask, and stirring was started.

And (3) dropwise adding 72.9g of concentrated sulfuric acid (1eq) with the mass concentration of 98.3% into the three-neck flask at the temperature of 20-30 ℃, controlling the internal temperature at 20-30 ℃, and preserving heat for 1h after dropwise adding is finished for 2 h.

Adding 50.3g of NaNO into the three-mouth bottle in batches (2 g each time) at the temperature of 20-30 DEG C₂Solid (1eq), 2h for addition.

After the addition is finished, heating to 78 ℃ for reflux, reacting for 6 hours in the state, and obtaining a second reaction solution after the reaction is finished.

Carrying out rotary evaporation on the second reaction liquid to recover most of ethanol; adding 500g of water and 500g of methyl tert-butyl ether into the rotary evaporated product, stirring, standing, separating liquid, washing the separated organic phase once with 500g of saturated sodium chloride solution, filtering with anhydrous sodium sulfate, carrying out rotary evaporation, and finally carrying out vacuum rectification with a water pump at the top temperature of 85-86 ℃ to obtain 151g of colorless liquid.

The colorless liquid obtained was subjected to Gas Chromatography (GC) and Hydrogen Nuclear Magnetic Resonance (HNMR) detection to determine its structural formula and purity. The colorless liquid obtained was determined by HNMR to be 1-bromo-3-chloro-5- (trifluoromethyl) benzene, 99% pure by GC and 80% calculated yield.

Synthesis of (tri) 3-chloro-5-trifluoromethyl trifluoro acetophenone

Under the protection of nitrogen, adding 700g of tetrahydrofuran, 17g of magnesium chips (1.2eq) and 1g of iodine into a 3L three-necked bottle, adding 15.1g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.1eq, total 1eq) into the three-necked bottle, heating to 50-60 ℃, stopping heating after initiation, maintaining the internal temperature at 50-60 ℃ by utilizing reaction heat release, slowly adding the rest 135.9g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.9eq, total 1eq) dropwise after the raw materials in the bottle are reacted, keeping the temperature for reaction after 1-3 h dropwise addition is finished, monitoring the reaction process of the 1-bromo-3-chloro-5- (trifluoromethyl) benzene in a gas phase, and monitoring and displaying that: the reaction is carried out for 2h, and after the 1-bromo-3-chloro-5- (trifluoromethyl) benzene reaction is finished, the reaction solution is cooled to 20 ℃ at the moment, so that the Grignard reagent solution is obtained.

Under the protection of nitrogen, under the condition of continuous stirring, adding 350g of tetrahydrofuran into the other 3L three-necked bottle, cooling to the internal temperature of-70 ℃ and keeping, adding 146.7g of trifluoroacetic anhydride (1.2eq), then slowly dropwise adding the Grignard reagent solution, controlling the internal temperature to be-70 ℃ to-60 ℃, and after 1-2 h of dropwise addition, keeping the temperature and reacting for 2h to obtain a third reaction solution.

And naturally heating the third reaction solution to 20 ℃, dropwise adding 700g of a dilute hydrochloric acid solution with the mass fraction of 7% into the third reaction solution, taking the dropwise adding time for 20min, adding 300g of methyl tert-butyl ether, stirring, standing for liquid separation, washing an organic phase obtained by separation with 500g of a saturated sodium chloride solution once, drying with anhydrous sodium sulfate, filtering, carrying out rotary evaporation to dryness, and finally carrying out reduced pressure rectification with a water pump, wherein the top temperature is 82-83 ℃, and taking 111g of a colorless liquid.

The colorless liquid obtained was subjected to Gas Chromatography (GC) and Hydrogen Nuclear Magnetic Resonance (HNMR) detection to determine its structural formula and purity. HNMR confirms that the obtained colorless liquid is 3-chloro-5-trifluoromethyl trifluoro acetophenone, the GC finds that the purity is 99 percent, and the calculated yield is 69 percent.

In the above embodiment, the internal temperature of-80 to-60 ℃ can be controlled by placing the reaction vessel containing the solution in a liquid nitrogen ethanol bath; and other cooling control, such as cooling to 0 ℃ and 20 ℃ or controlling the internal temperature to 0-5 ℃ and 20-30 ℃, can be realized by placing the reaction vessel filled with the solution in a frozen salt bath.

It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that the invention is described with reference to exemplary embodiments, but rather the words used therein are words of description and illustration, rather than words of limitation. The invention can be modified, as prescribed, within the scope of the claims and without departing from the scope and spirit of the invention. Although the invention has been described herein with reference to particular means, materials and embodiments, the invention is not intended to be limited to the particulars disclosed herein, but rather extends to all other methods and applications having the same functionality.