CN113636919B - Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone - Google Patents

Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone Download PDF

Info

Publication number
CN113636919B
CN113636919B CN202110966643.1A CN202110966643A CN113636919B CN 113636919 B CN113636919 B CN 113636919B CN 202110966643 A CN202110966643 A CN 202110966643A CN 113636919 B CN113636919 B CN 113636919B
Authority
CN
China
Prior art keywords
chloro
trifluoromethyl
reaction
bromo
benzene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202110966643.1A
Other languages
Chinese (zh)
Other versions
CN113636919A (en
Inventor
赵云
闾肖波
陈鹏飞
刘陈阳
刘杰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Sinofluoro Scientific Co ltd
Original Assignee
Shanghai Sinofluoro Scientific Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Sinofluoro Scientific Co ltd filed Critical Shanghai Sinofluoro Scientific Co ltd
Priority to CN202110966643.1A priority Critical patent/CN113636919B/en
Publication of CN113636919A publication Critical patent/CN113636919A/en
Application granted granted Critical
Publication of CN113636919B publication Critical patent/CN113636919B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds

Abstract

The invention discloses a method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone, which comprises the following steps: the o-aminotrifluorotoluene is firstly brominated and then chlorinated to obtain 4-bromo-2-chloro-6-trifluoromethyl aniline; diazotizing 4-bromo-2-chloro-6-trifluoromethylaniline, and treating with hypophosphorous acid or ethanol to obtain deaminated compound 1-bromo-3-chloro-5- (trifluoromethyl) benzene; the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is made into Grignard reagent by magnesium chips, and nucleophilic reaction is carried out with acylating reagent to obtain 3-chloro-5-trifluoromethyl trifluoroacetophenone. The o-aminotrifluorotoluene as the initial material is a common chemical with low price, and the products obtained by each step of reaction have good purity and high yield, have relatively small environmental pollution and are expected to be used for large-scale industrial production.

Description

Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone
Technical Field
The invention relates to a pesticide (such as pest repellent) intermediate containing fluorine element, in particular to a synthesis method of fluorine-containing fine chemicals.
Background
Because of the unique property of fluorine, the fluorine-containing compound has excellent performance and is widely applied to medicines, pesticides, materials and the like. And China has natural advantages on fluorine resources, so that fluorine-containing fine chemicals serving as organic intermediates gradually show great growth potential.
Afrana (afoxollan), commercially available as nikoshi (NexGard), is the first line of market in china by the company bringen, 8 in 2017 for oral insect repellents for dogs against both parasites, ticks and fleas. The compound belongs to isoxazolines, and the action principle is that the death is caused by inhibiting GABA chloride ion channels of arthropods and then highly exciting nerves. The number of the current Chinese pet dogs exceeds 6200 ten thousand. Dogs are active, are susceptible to infection by a variety of parasites, and can be harmful to their health and the health of the feeding owners, thus requiring a series of measures to kill the parasites. Fleas cannot spawn because of killing fleas after taking afrana for two hours, environmental pollution is avoided, fleas can be effectively prevented from spawning after lasting five weeks, and meanwhile, 8 common cicada insects can be repelled and killed, and the effect lasts for more than 1 month.
3-chloro-5-trifluoromethyl trifluoroacetophenone is an important intermediate for synthesizing aforana, contains relatively active trifluoroacetyl groups, and can 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 reported in literature, and particularly, has potential to be applied to a process route for large-scale industrial production (such as low production cost), and has no reports, so that development and research are needed.
Disclosure of Invention
In view of this, the present invention has been made in an effort to explore a new synthetic route and process for 3-chloro-5-trifluoromethyl trifluoroacetophenone, which can effectively reduce the cost by using a cheap and easily available compound as a starting material, and perform a reaction using a relatively safe solvent while achieving a high reaction yield, thereby being more likely to be used in industrial production.
The present invention contemplates the preparation of 3-chloro-5-trifluoromethyl trifluoroacetophenone by reacting a corresponding organometallic reagent derived from 3-bromo-5-chlorotrifluorotoluene of formula (II) below with an acylating reagent.
However, the compound 3-bromo-5-chlorotrifluorotoluene of formula (II) is not a readily available compound and is commercially expensive (chemical book shows 3-bromo-5-chlorotrifluorotoluene, 98% purity, 100g package, selling price 2120 yuan). This selling price is quite expensive, approaching or even exceeding the price of the product 3-chloro-5-trifluoromethyl trifluoroacetophenone, so that the production cost of the process route with 3-bromo-5-chlorotrifluorotoluene as starting material is very high, and it is obviously impossible to use it in large-scale industrial production. Meanwhile, no report is made in the current literature on the synthesis process of 3-bromo-5-chlorotrifluorotoluene, so that the preparation of the 3-bromo-5-chlorotrifluorotoluene can be peeped. Based on the above reality, the search for this synthetic route has been stopped by most studies.
However, the invention unexpectedly discovers a new synthetic route in repeated exploration: the o-aminotrifluorotoluene is taken as the initial raw material, 3-chloro-5-trifluoromethyl trifluoroacetophenone can be prepared with low cost through simple three-step treatment, the single-step yield can reach 97 percent, the purities of each intermediate product and the final product reach 98 to 99 percent, and the method is expected to be applied to large-scale industrial production.
Specifically, the invention adopts the following technical scheme to realize the aim:
a method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone, comprising the following steps:
step S1: the o-aminotrifluorotoluene is firstly brominated and then chlorinated to obtain 4-bromo-2-chloro-6-trifluoromethyl aniline;
step S2: diazotizing 4-bromo-2-chloro-6-trifluoromethylaniline, and treating with hypophosphorous acid or ethanol to obtain deaminated compound 1-bromo-3-chloro-5- (trifluoromethyl) benzene;
step S3: the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is made into Grignard reagent by magnesium chips, and nucleophilic reaction is carried out with acylating reagent, thus obtaining 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-aminotrifluorotoluene, a first solvent and a first catalyst into a first reaction container, continuously stirring, controlling the internal temperature to be 0-5 ℃, adding a brominating reagent into the mixture, and preserving the heat for 1-4 hours after the addition; naturally heating to an internal temperature of 25-30 ℃, and preserving heat for bromination reaction for 1-6 h; after the bromination reaction is finished, controlling the internal temperature to be 25-30 ℃, adding a chlorinating reagent into the internal temperature, and preserving the temperature for carrying out the chlorination reaction for 5-20 hours after the adding; after the chlorination reaction is finished, performing first post-treatment on the obtained first reaction liquid to obtain 4-bromo-2-chloro-6-trifluoromethyl aniline;
the first solvent is selected from at least one of 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 chloride, NBS (N-bromosuccinimide) and dibromohydantoin; the chloro reagent 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-aminotrifluorotoluene is (2-10): 1, the mole ratio of the first catalyst to the o-aminotrifluorotoluene is (0.001 to 0.01): 1, the molar ratio of effective bromine to o-aminotrifluorotoluene in the bromination reagent is (0.95-1.15): 1, the molar ratio of available chlorine to o-aminotrifluorotoluene in the chloro reagent is (0.95-1.15): 1.
in some embodiments, in step S1, the brominating agent is slowly added, for example, a dropwise addition or multiple addition in batches may be adopted; the chlorinating agent is slowly added, for example, by dropwise addition or multiple addition in batches.
In some embodiments, in step S1, the first post-processing procedure is: pouring the first reaction liquid into ice water or water, stirring in a first extraction solvent, standing for liquid separation, washing an organic phase obtained by separation by using a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate, filtering, and finally rotationally evaporating to dryness to obtain a first intermediate product of 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 extraction solvent may not be added during the first post-treatment.
In some embodiments, in step S1, the first reaction vessel is provided with an off-gas absorbing device.
In some embodiments, step S2 includes:
sequentially adding the 4-bromo-2-chloro-6-trifluoromethylaniline prepared in the step S1 and water into a second reaction container, dropwise adding sulfuric acid into the second reaction container under continuous stirring, controlling the internal temperature to be 20-30 ℃, and preserving the heat for 1-2 h after the dropwise adding is finished; then cooling to 0-5 ℃, dropwise adding sodium nitrite aqueous solution into the mixture, controlling the internal temperature to be 0-5 ℃, and carrying out heat preservation reaction for 1-2 h after the dropwise adding is finished to obtain diazonium salt solution;
adding an aqueous solution of hypophosphorous acid into a third reaction container, dropwise adding the diazonium salt solution into the third reaction container under continuous stirring, controlling the internal temperature to be 20-30 ℃, carrying out heat preservation reaction 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, a step of; the molar ratio of sulfuric acid to 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 solute (sodium nitrite) to solvent (water) in the sodium nitrite aqueous solution is (0.5-1): 1, a step of; the mass concentration of the hypophosphorous acid aqueous solution is 30-50%.
In some embodiments, in step S2, the mass concentration of sulfuric acid is 98.3%.
In some embodiments, in step S2, sulfuric acid is added by slow dropwise addition. For example, in one embodiment, 246g of 98.3% strength by mass concentrated sulfuric acid is added dropwise over a period of 1 to 3 hours.
In some embodiments, in step S2, the mass concentration of the aqueous hypophosphorous acid solution is 50%.
In some embodiments, in step S2, the second post-processing procedure is:
and adding dichloromethane into the second reaction solution, stirring, standing for separating, washing an organic phase obtained by separation by using a NaOH solution with the mass concentration of 1-20%, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, finally rotationally evaporating, and performing reduced pressure rectification at the top temperature of 85-86 ℃.
In some embodiments, in step S2, the NaOH solution has a mass concentration of 3%.
Alternatively, step S2 may take another scheme:
that is, in other specific examples, step S2 includes:
sequentially adding the 4-bromo-2-chloro-6-trifluoromethyl aniline prepared in the step S1 and ethanol into a second reaction container, dropwise adding sulfuric acid into the second reaction container under continuous stirring, controlling the internal temperature to be 20-30 ℃, and preserving the heat for 0.5-2 h after the dropwise adding is finished; adding NaNO into the second reaction vessel in batches at 20-30 DEG C 2 Heating the solid to reflux after the solid is added, keeping the reflux temperature for reacting for 4-7 hours to obtain a second reaction liquid, and obtaining 1-bromo-3-chloro-5- (trifluoromethyl) benzene through second post-treatment;
wherein the mass ratio of the ethanol to the 4-bromo-2-chloro-6-trifluoromethylaniline is (3-5): 1, a step of; the molar ratio of sulfuric acid to 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 dosage of the sodium nitrite to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-1.4): 1.
in step S2, naNO is added in portions 2 Solids, meaning that a small amount of material is dosed at intervals of several times, e.g. in a specific example, 2g,64g nano per charge 2 The addition of the solid took 2h.
In some embodiments, in step S2, sulfuric acid is added by slow dropwise addition. For example, in one embodiment, 72.9g of 98.3% strength by mass concentrated sulfuric acid is added dropwise over 2 hours.
In some embodiments, in step S2, the mass concentration of sulfuric acid is 98.3%.
In some embodiments, 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 tertiary butyl ether into the product after rotary steaming, stirring, standing for separating liquid, separating an obtained organic phase, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, rotary steaming, and performing reduced pressure rectification at the top temperature of 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 container, firstly adding a first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2, heating to 50-60 ℃, stopping heating after initiation, maintaining the internal temperature at 50-60 ℃ by utilizing reaction heat release, dripping the second batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2 into the reaction container after reaction, preserving heat for reaction for 1-3 hours after the dripping, and cooling to 15-25 ℃ after the reaction is finished, thus obtaining a Grignard reagent solution;
under the protection of nitrogen, adding a third solvent and an acylating reagent into a fifth reaction container under the continuous stirring, controlling the internal temperature to be between-85 ℃ and-55 ℃, dripping the Grignard reagent solution into the fifth reaction container, controlling the internal temperature to be between-80 ℃ and-60 ℃, and carrying out heat preservation reaction for 1-4 hours after the dripping is finished to obtain a third reaction solution; performing third post-treatment on the third reaction liquid to obtain 3-chloro-5-trifluoromethyl trifluoroacetophenone;
the second solvent is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tertiary butyl ether, the initiator is iodine or/and 1, 2-dibromoethane, the third solvent is the same as the second solvent, and the acylating agent is selected from 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, wherein the mass ratio of the third solvent to the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-5): 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): the molar ratio of the acylating agent to the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1 to 1.5): 1, a step of; the first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is 1/30 to 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 refers to the sum of the first batch and the second batch.
In some embodiments, in step S3, the first amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is added by rapid dropwise addition, and the second amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is added by slow dropwise addition.
In some embodiments, in step S3, the grignard reagent solution is added by slow dropwise addition.
In some embodiments, in step S3, the third post-processing procedure is:
naturally heating the third reaction liquid to an internal temperature of 10-20 ℃, dropwise adding a dilute hydrochloric acid solution with a mass concentration of 5-10%, adding a third extraction solvent, stirring, standing for liquid separation, washing an organic phase obtained by separation by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, spin-drying, rectifying under reduced pressure, and standing at a top temperature of 82-83 ℃.
In some embodiments, the third extraction solvent is methyl tert-butyl ether or 2-methyltetrahydrofuran.
In some embodiments, the diluted 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, effective bromine in a bromination reagent refers to a bromine element corresponding to a bromine cation in the bromination reagent, and also refers to oxidation state bromine contained in the bromination reagent.
In the present invention, the effective chlorine in the chlorinated reagent means chlorine element corresponding to the generation of chlorine positive ions in the chlorinated reagent, and may also mean oxidation state chlorine contained in the chlorinated reagent.
The invention also provides the 3-chloro-5-trifluoromethyl trifluoroacetophenone prepared by the synthesis method.
In the synthesis method, in the step S1, bromine and chlorine are skillfully added to para position and ortho position of amino respectively by utilizing the amino positioning effect, so that side reactions are effectively avoided, the purity of the synthesized 1-bromo-3-chloro-5- (trifluoromethyl) benzene is more than 95%, and the generation of two impurities of 1, 3-dichloro-5-trifluoromethyl benzene and 1, 3-dibromo-5-trifluoromethyl benzene, which are similar to the intermediate in nature, is effectively avoided, and the difficulty of post-treatment and purification is greatly reduced; in addition, the bromination and the chlorination are continuously carried out, and can be completed in the same reaction vessel, and the brominated intermediate does not need to be separated, so that the complicated steps of post-treatment can be reduced; in the step S2, diazotization is utilized to directly deaminize, and a complex process of protecting amino and then deaminizing is not needed to be adopted; in the step S3, concentrated sulfuric acid is added dropwise, so that the safety of the reaction is ensured, and the 3-chloro-5-trifluoromethyl trifluoroacetophenone is prepared by carrying out a low-temperature Grignard reaction under safe reaction conditions. The synthesis method takes the o-aminotrifluorotoluene with wide sources and low price as a reaction raw material, and each step of reaction can maximally obtain the intermediate with the purity of 98-99 percent, so that the total yield of the whole reaction is high, the purity of the final product is higher than 98 percent, the economic benefit is obvious, the environmental pollution is less, 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 synthesis method, the steps of the whole route are not more, only three times of post-treatment are needed, the post-treatment process of industrial production is simplified, the production time and cost are greatly saved, the reaction mechanism is clear, 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 expansion production is convenient.
2. The method has the advantages of wide sources of the initial raw materials, easy acquisition and low price, can effectively reduce the production cost, has high reaction yield in each step, accords with the principle of atom economy, and has potential to be used 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 waste water and waste liquid by acid-base neutralization, can reduce the production and treatment cost, reduces the environmental pollution, and is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in the step (one) of example 1, identified as 4-bromo-2-chloro-6-trifluoromethylaniline.
FIG. 2 is a nuclear magnetic resonance spectrum of the product obtained in the step (II) of example 1, which was identified as a nuclear magnetic resonance spectrum of 1-bromo-3-chloro-5- (trifluoromethyl) benzene.
FIG. 3 is a nuclear magnetic resonance spectrum of the product obtained in the step (III) of example 1, which was identified as a nuclear magnetic resonance spectrum of 3-chloro-5-trifluoromethyl trifluoroacetophenone.
Detailed Description
For a better description of the present invention, the technical solution of the present invention will be easily understood, and the present invention will be further described in detail with reference to the accompanying drawings and the specific embodiments. It is to be understood that the following examples are provided for illustration only and are not intended to represent or limit the scope of the invention as claimed.
The reagents or apparatus used in the examples below are conventional products available commercially without the manufacturer's knowledge. In the invention, all the raw materials are commercial products. Wherein the commercial price of the o-aminotrifluorotoluene is about 6 ten thousand yuan/ton.
In the following examples, the gas phase monitoring reaction progress, which means the gas phase monitoring of the residual amount of the reaction raw material, was achieved by monitoring the value of the raw material peak-exiting integral area/(raw material peak-exiting integral area+product peak-exiting integral area) on the GC spectrum. When the value is monitored to be < 0.5%, this means that the remaining amount of the reaction raw material is < 0.5%, and it can be regarded that the reaction is completed.
Example 1
Synthesis of (one) 4-bromo-2-chloro-6-trifluoromethylaniline
200g of o-aminotrifluorotoluene (1 eq), 1kg of methylene chloride and 0.1g of iron powder were successively added to a 2L three-necked flask equipped with a tail gas absorber; stirring is started, the temperature is reduced to 0 ℃, 144.7g of cold (about-15 ℃) bromine chloride (1.01 eq) is dripped into a three-mouth bottle, the internal temperature is controlled to be 0-5 ℃, and the temperature is kept for 2 hours after the dripping is finished; then naturally heating to 25 ℃, preserving heat for bromination reaction, and monitoring the reaction progress of raw material o-aminotrifluorotoluene in the bromination reaction in a gas phase, wherein the monitoring shows that: the bromination reaction is carried out for 2 hours, and the raw material o-aminotrifluorotoluene is reacted completely.
After the o-aminotrifluorotoluene is reacted, 169.2g of sulfonyl chloride (1.01 eq) is dripped into the reaction liquid at 25 ℃, the internal temperature is controlled at 25-30 ℃, the reaction liquid is preserved for chlorination reaction after dripping for 1-3 hours, and the reaction progress of the raw material 4-bromo-2-trifluoromethyl aniline in the chlorination reaction is monitored by gas phase, and the monitoring shows that: the chlorination reaction is carried out for 12 hours, and the reaction of the raw material 4-bromo-2-trifluoromethyl aniline is completed.
After the reaction of 4-bromo-2-trifluoromethylaniline is completed, the obtained first reaction solution is poured into 1kg of ice water, stirred, stood still for liquid separation, and the obtained organic phase is separated and sequentially treated with 500g of saturated NaHCO 3 Washing the solution once, washing the solution once with 500g of saturated sodium chloride solution, drying the solution with anhydrous sodium sulfate, filtering the solution, and evaporating the solution by rotating the solution to obtain 337g of oily liquid.
The obtained oily liquid was subjected to Gas Chromatography (GC) and nuclear magnetic resonance hydrogen spectroscopy (HNMR) to determine its structural formula and purity. The nuclear magnetic resonance hydrogen spectrum is shown in FIG. 1, in which 1H NMR (400 MHz; DMSO-d 6) delta=7.74 (d, J=1.6 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 5.90 (s, 2H). From the analysis of FIG. 1, it was determined that the resulting oily liquid was 4-bromo-2-chloro-6-trifluoromethylaniline. Purity 98% by GC and calculated yield 97%.
Synthesis of (di) 1-bromo-3-chloro-5- (trifluoromethyl) benzene
To a 5L three-necked flask, 337g of 4-bromo-2-chloro-6-trifluoromethylaniline (1 eq) and 1.35kg of water were successively added, and stirring was started. At room temperature (20-30 ℃), 246g of 98.3% concentrated sulfuric acid (2 eq) is slowly added dropwise, the internal temperature is controlled at 20-30 ℃, and the temperature is kept for 1h after the completion of the dropwise addition. Then cooling to 0 ℃, and dripping NaNO 2 Aqueous solution (93.2 g NaNO) 2 Dissolving in 93.2g of water) (1.1 eq) and controlling the internal temperature at 0-5 ℃ for 1-4 h, then preserving the heat for reaction for 1h after the dripping is finished, and detecting that the reaction liquid has oxidizing property by using starch potassium iodide test paper, thus indicating that the reaction liquid is prepared into diazonium salt water solution.
486g of hypophosphorous acid aqueous solution (3 eq) with the mass concentration of 50% is added into another 5L three-mouth bottle, stirring is started, the diazonium salt aqueous solution is dripped into the bottle at room temperature (20-30 ℃), the internal temperature is controlled to be 20-30 ℃, and the bottle is subjected to heat preservation reaction for 12 hours after dripping is finished for 2-4 hours, so that a second reaction solution is obtained.
Adding 1.3kg of dichloromethane into the second reaction solution, stirring, standing for separating, separating an obtained organic phase, washing 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, rotationally evaporating to dryness, and finally rectifying under reduced pressure by a water pump at the top temperature of 85-86 ℃ to obtain 226g of colorless liquid.
The obtained colorless liquid was subjected to Gas Chromatography (GC) and nuclear magnetic resonance hydrogen spectroscopy (HNMR) to determine its structural formula and purity. The spectrum of the nuclear magnetic resonance hydrogen spectrum is shown in FIG. 2, and in FIG. 2, 1H NMR (400 MHz; CDCl 3 ) δ=7.70 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H). From the analysis of FIG. 2, it was determined that the colorless liquid obtained was 1-bromo-3-chloro-5- (trifluoromethyl) benzene. Purity 99% by GC and calculated yield 71%.
Synthesis of (tri) 3-chloro-5-trifluoromethyl trifluoroacetophenone
Under the protection of nitrogen, 1kg of 2-methyltetrahydrofuran, 24.6g of magnesium chips (1.16 eq) and 1g of 1, 2-dibromoethane are added into a 3L three-necked flask, 22.6g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.1 eq, total 1 eq) is firstly added into the three-necked flask, the three-necked flask is heated to 50-60 ℃, after initiation, heating is stopped, the internal temperature is maintained at 50-60 ℃ by utilizing reaction exotherm, after the reaction of raw materials in the flask is completed, the rest 203.4g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.9 eq, total 1 eq) is slowly added dropwise, the three-necked flask is heated for reaction after 1-3 h dropwise, and the reaction progress of the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is monitored to show that: and (3) after the reaction is carried out for 2 hours, the reaction of the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is finished, and at the moment, the reaction solution is cooled to 20 ℃ to obtain the Grignard reagent solution.
Under the protection of nitrogen, 500g of 2-methyltetrahydrofuran is added into another 3L three-mouth bottle under the continuous stirring, the temperature is reduced to-80 ℃ and kept, 127g of trifluoroacetyl chloride gas (1.1 eq) is introduced, then the Grignard reagent solution is slowly added into the bottle, the internal temperature is controlled to-80 ℃ to-70 ℃, and the reaction is carried out for 2 hours after the 1-2 hours of dropwise addition, so as to obtain a third reaction solution.
And naturally heating the third reaction liquid to 20 ℃, dropwise adding 1kg of a dilute hydrochloric acid solution with the mass concentration of 7% into the third reaction liquid for 20min, adding 300g of methyl tertiary butyl ether, stirring, standing for liquid separation, washing the separated organic phase once with 500g of saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin-drying, and finally carrying out reduced pressure rectification with a water pump, wherein the top temperature is 82-83 ℃, thus obtaining 180g of colorless liquid.
The obtained colorless liquid was subjected to Gas Chromatography (GC) and nuclear magnetic resonance hydrogen spectroscopy (HNMR) to determine its structural formula and purity. The spectrum of the nuclear magnetic resonance hydrogen spectrum is shown in FIG. 3, and in FIG. 3, 1H NMR (400 MHz; CDCl 3 ) δ=8.21-8.19 (m, 2H), 7.95 (s, 1H). From the analysis of FIG. 3, it was confirmed that the colorless liquid obtained was 3-chloro-5-trifluoromethyl trifluoroacetophenone, purity by GC was 99%, and calculated yield was 75%.
Example 2
Synthesis of (one) 4-bromo-2-chloro-6-trifluoromethylaniline
To a 2L three-necked flask, 120g of o-aminotrifluorotoluene (1 eq), 800g of acetonitrile and 0.1g of aluminum trichloride were successively charged, and stirring was started.
Cooling to 0 ℃, adding 117.1g dibromohydantoin solid (0.55 eq) in batches (3 g each time and 2h for feeding), controlling the internal temperature to be 0-5 ℃, and preserving the heat for 4h after the addition; then naturally heating to 25 ℃, preserving heat for bromination reaction, and monitoring the reaction progress of raw material o-aminotrifluorotoluene in the bromination reaction in a gas phase, wherein the monitoring shows that: the bromination reaction is carried out for 5 hours, and the reaction of the raw material o-aminotrifluorotoluene is completed.
After the o-aminotrifluorotoluene is reacted, 64g of TCCA solid (0.37 eq) is continuously added into the reaction liquid in batches (1 g each time and 3h for feeding) at 25 ℃, the internal temperature is controlled to be 25-30 ℃, the chlorination reaction is carried out after the addition, the reaction progress of the raw material 4-bromo-2-trifluoromethyl aniline in the chlorination reaction is monitored in a gas phase, and the monitoring shows that: the chlorination reaction is carried out for 16 hours, and the reaction of the raw material 4-bromo-2-trifluoromethyl aniline is completed.
After the reaction of the 4-bromo-2-trifluoromethylaniline is finished, the obtained first reaction solution is poured into 1kg of water, 500g of ethyl acetate is added for stirring, the mixture is stood for liquid separation, and the obtained organic phase is separated and sequentially treated with 500g of saturated NaHCO 3 Washing the solution once, washing the solution with 500g of saturated sodium chloride solution three times, and then using anhydrous sodium sulfateDrying, filtering, and rotary evaporating to dryness to obtain 200g oily liquid.
The obtained oily liquid was subjected to Gas Chromatography (GC) and nuclear magnetic resonance hydrogen spectroscopy (HNMR) to determine its structural formula and purity. HNMR determined that the resulting oily liquid was 4-bromo-2-chloro-6-trifluoromethylaniline, and the purity by GC was 98%, calculated to be 96%.
Synthesis of (di) 1-bromo-3-chloro-5- (trifluoromethyl) benzene
200g of 4-bromo-2-chloro-6-trifluoromethylaniline (1 eq) and 800g of ethanol were successively added to a 3L three-necked flask, and stirring was started.
72.9g of 98.3% concentrated sulfuric acid (1 eq) is dripped into the three-mouth bottle at 20-30 ℃, the internal temperature is controlled at 20-30 ℃, and the temperature is kept for 1h after the dripping is finished.
50.3g NaNO was added to the above three-necked flask in portions (2 g each) at 20 to 30℃C 2 Solid (1 eq) was added 2h.
After the addition, the mixture is heated to 78 ℃ for reflux, and reacted for 6 hours in the state, and a second reaction liquid is obtained after the reaction is finished.
Performing rotary evaporation on the second reaction liquid to recover most of ethanol; adding 500g of water and 500g of methyl tertiary butyl ether into the product after rotary evaporation, stirring, standing for liquid separation, washing the separated organic phase once by using 500g of saturated sodium chloride solution, filtering by using anhydrous sodium sulfate, rotary evaporating to dryness, and finally decompressing and rectifying by using a water pump, wherein the top temperature is 85-86 ℃, and obtaining 151g of colorless liquid.
The obtained colorless liquid was subjected to Gas Chromatography (GC) and nuclear magnetic resonance hydrogen spectroscopy (HNMR) to determine its structural formula and purity. HNMR determined that the colorless liquid obtained was 1-bromo-3-chloro-5- (trifluoromethyl) benzene, and the purity by GC was 99%, calculated to be 80%.
Synthesis of (tri) 3-chloro-5-trifluoromethyl trifluoroacetophenone
700g of tetrahydrofuran, 17g of magnesium dust (1.2 eq) and 1g of iodine are added into a 3L three-necked flask under the protection of nitrogen, 15.1g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.1 eq) is firstly added into the three-necked flask, the three-necked flask is heated to 50 to 60 ℃ and stopped after initiation, the internal temperature is maintained at 50 to 60 ℃ by utilizing the reaction exotherm, after the reaction of the raw materials in the flask is completed, the rest 135.9g of 1-bromo-3-chloro-5- (trifluoromethyl) benzene (0.9 eq) is slowly added dropwise, the three-necked flask is heated for reaction after 1 to 3h, and the reaction progress of the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is monitored to show that: and (3) after the reaction is carried out for 2 hours, the reaction of the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is finished, and at the moment, the reaction solution is cooled to 20 ℃ to obtain the Grignard reagent solution.
Under the protection of nitrogen, 350g of tetrahydrofuran is added into another 3L three-mouth bottle under the continuous stirring, the temperature is reduced to-70 ℃ and kept, 146.7g of trifluoroacetic anhydride (1.2 eq) is added, then the Grignard reagent solution is slowly added into the bottle, the internal temperature is controlled to be-70 ℃ to-60 ℃, and the reaction is carried out for 2 hours after the dripping is finished, so as to obtain a third reaction solution.
Naturally heating the third reaction liquid to 20 ℃, dripping 700g of 7% by mass of dilute hydrochloric acid solution into the third reaction liquid for 20min, adding 300g of methyl tertiary butyl ether, stirring, standing for liquid separation, washing the separated organic phase once with 500g of saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, rotationally evaporating to dryness, decompressing and rectifying by a water pump, and taking 111g of colorless liquid at the top temperature of 82-83 ℃.
The obtained colorless liquid was subjected to Gas Chromatography (GC) and nuclear magnetic resonance hydrogen spectroscopy (HNMR) to determine its structural formula and purity. HNMR confirmed that the colorless liquid obtained was 3-chloro-5-trifluoromethyl trifluoroacetophenone, and the purity by GC was 99%, and the calculated yield was 69%.
In the above examples, the internal temperature control at-80 to-60℃can be achieved by placing the reaction vessel containing the solution in a bath of liquid nitrogen and ethanol; other cooling control, such as cooling to 0 deg.c, 20 deg.c, or controlling the inner temperature at 0-5 deg.c, 20-30 deg.c, etc. may be realized through setting the reaction container with the solution inside ice 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 the exemplary embodiments, but are to be understood as meaning that the words which have been used are words of description and illustration, rather than words of limitation. Modifications may be made to the invention as defined in the appended claims, and the invention may be modified without departing from the scope and spirit of the invention. Although the invention is described herein with reference to particular means, materials and embodiments, the invention is not intended to be limited to the particulars disclosed herein, as the invention extends to all other means and applications which perform the same function.

Claims (9)

1. A method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone, which is characterized by comprising the following steps:
step S1: the o-aminotrifluorotoluene is firstly brominated and then chlorinated to obtain 4-bromo-2-chloro-6-trifluoromethyl aniline;
step S2: diazotizing 4-bromo-2-chloro-6-trifluoromethylaniline, and treating with hypophosphorous acid or ethanol to obtain deaminated compound 1-bromo-3-chloro-5- (trifluoromethyl) benzene;
step S3: using magnesium scraps to prepare a Grignard reagent from 1-bromo-3-chloro-5- (trifluoromethyl) benzene, and carrying out nucleophilic reaction with an acylating reagent to obtain 3-chloro-5-trifluoromethyl trifluoroacetophenone;
wherein, step S1 includes:
sequentially adding o-aminotrifluorotoluene, a first solvent and a first catalyst into a first reaction container, continuously stirring, controlling the internal temperature to be 0-5 ℃, adding a brominating reagent into the mixture, and preserving the heat for 1-4 hours after the addition; naturally heating to an internal temperature of 25-30 ℃, and preserving heat for bromination reaction for 1-6 h; after the bromination reaction is finished, controlling the internal temperature to be 25-30 ℃, adding a chlorinating reagent into the internal temperature, and preserving the temperature for carrying out the chlorination reaction for 5-20 hours after the adding; after the chlorination reaction is finished, performing first post-treatment on the obtained first reaction liquid to obtain 4-bromo-2-chloro-6-trifluoromethyl aniline;
the first solvent is selected from at least one of 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 chloride, 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-aminotrifluorotoluene is (2-10): 1, the mole ratio of the first catalyst to the o-aminotrifluorotoluene is (0.001 to 0.01): 1, the molar ratio of effective bromine to o-aminotrifluorotoluene in the bromination reagent is (0.95-1.15): 1, the molar ratio of available chlorine to o-aminotrifluorotoluene in the chloro reagent is (0.95-1.15): 1.
2. the method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 1, wherein in step S1, the first post-treatment process is:
pouring the first reaction liquid into ice water or water, stirring in a first extraction solvent, standing for liquid separation, washing an organic phase obtained by separation by using a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate, filtering, and finally rotationally evaporating to dryness to obtain a first intermediate product of 4-bromo-2-chloro-6-trifluoromethylaniline.
3. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 2, wherein the first extraction solvent is dichloromethane, ethyl acetate or n-hexane.
4. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 1, wherein step S2 comprises:
sequentially adding the 4-bromo-2-chloro-6-trifluoromethylaniline prepared in the step S1 and water into a second reaction container, dropwise adding sulfuric acid into the second reaction container under continuous stirring, controlling the internal temperature to be 20-30 ℃, and preserving the heat for 1-2 h after the dropwise adding is finished; then cooling to 0-5 ℃, dropwise adding sodium nitrite aqueous solution into the mixture, controlling the internal temperature to be 0-5 ℃, and carrying out heat preservation reaction for 1-2 h after the dropwise adding is finished to obtain diazonium salt solution; adding an aqueous solution of hypophosphorous acid into a third reaction container, dropwise adding the diazonium salt solution into the third reaction container under continuous stirring, controlling the internal temperature to be 20-30 ℃, carrying out heat preservation reaction 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, a step of; the molar ratio of sulfuric acid to 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, a step of; the mass concentration of the hypophosphorous acid aqueous solution is 30-50%.
5. A method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 3, wherein in step S2, the second post-treatment process is:
and adding dichloromethane into the second reaction solution, stirring, standing for separating, washing an organic phase obtained by separation by using a NaOH solution with the mass concentration of 1-20%, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, rotationally evaporating, and performing reduced pressure rectification at the top temperature of 85-86 ℃.
6. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 1, wherein step S2 comprises:
sequentially adding the 4-bromo-2-chloro-6-trifluoromethyl aniline prepared in the step S1 and ethanol into a second reaction container, dropwise adding sulfuric acid into the second reaction container under continuous stirring, controlling the internal temperature to be 20-30 ℃, and preserving the heat for 0.5-2 h after the dropwise adding is finished; adding NaNO into the second reaction vessel in batches at 20-30 DEG C 2 Heating the solid to reflux after the solid is added, keeping the reflux temperature for reacting for 4-7 hours to obtain a second reaction liquid, and obtaining 1-bromo-3-chloro-5- (trifluoromethyl) benzene through second post-treatment;
wherein the mass ratio of the ethanol to the 4-bromo-2-chloro-6-trifluoromethylaniline is (3-5): 1, a step of; the molar ratio of sulfuric acid to 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 dosage of the sodium nitrite to the 4-bromo-2-chloro-6-trifluoromethylaniline is (1-1.4): 1.
7. the method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 6, wherein in step S2, the second post-treatment process is as follows:
and (3) after the second reaction liquid is subjected to rotary evaporation, adding water and methyl tertiary butyl ether into a product obtained after the rotary evaporation, stirring, standing for liquid separation, and sequentially washing an organic phase obtained by separation by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, rotationally evaporating, and then carrying out reduced pressure rectification at the top temperature of 85-86 ℃.
8. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 1, wherein step S3 comprises:
under the protection of nitrogen, adding a second solvent, magnesium chips and an initiator into a fourth reaction container, firstly adding a first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2, heating to 50-60 ℃, stopping heating after initiation, maintaining the internal temperature at 50-60 ℃ by utilizing reaction heat release, dripping the second batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene prepared in the step S2 into the reaction container after reaction, preserving heat for reaction for 1-3 hours after the dripping, and cooling to 15-25 ℃ after the reaction is finished, thus obtaining a Grignard reagent solution; under the protection of nitrogen, adding a third solvent and an acylating reagent into a fifth reaction container under the continuous stirring, controlling the internal temperature to be between-85 ℃ and-55 ℃, dripping the Grignard reagent solution into the fifth reaction container, controlling the internal temperature to be between-80 ℃ and-60 ℃, and carrying out heat preservation reaction for 1-4 hours after the dripping is finished to obtain a third reaction solution; performing third post-treatment on the third reaction liquid to obtain 3-chloro-5-trifluoromethyl trifluoroacetophenone;
the second solvent is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tertiary butyl ether, the initiator is iodine or/and 1, 2-dibromoethane, the third solvent is the same as the second solvent, and the acylating agent is selected from 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, wherein the mass ratio of the third solvent to the total amount of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1-5): 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): the molar ratio of the acylating agent to the 1-bromo-3-chloro-5- (trifluoromethyl) benzene is (1 to 1.5): 1, a step of; the first batch of 1-bromo-3-chloro-5- (trifluoromethyl) benzene is 1/30 to 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 refers to the sum of the first batch and the second batch.
9. The method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone according to claim 8, wherein in step S3, the third post-treatment process is as follows:
naturally heating the third reaction liquid to an internal temperature of 10-20 ℃, dropwise adding a dilute hydrochloric acid solution with a mass concentration of 5-10%, 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, rectifying under reduced pressure, and standing at a top temperature of 82-83 ℃; the third extraction solvent is methyl tertiary butyl ether or 2-methyltetrahydrofuran.
CN202110966643.1A 2021-08-23 2021-08-23 Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone Active CN113636919B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110966643.1A CN113636919B (en) 2021-08-23 2021-08-23 Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110966643.1A CN113636919B (en) 2021-08-23 2021-08-23 Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone

Publications (2)

Publication Number Publication Date
CN113636919A CN113636919A (en) 2021-11-12
CN113636919B true CN113636919B (en) 2023-10-24

Family

ID=78423433

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110966643.1A Active CN113636919B (en) 2021-08-23 2021-08-23 Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone

Country Status (1)

Country Link
CN (1) CN113636919B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115353499B (en) * 2022-10-21 2023-02-28 南京远淑医药科技有限公司 Synthetic method of 2-halomethyl-5-trifluoromethyl furan
CN115784858B (en) * 2022-12-21 2023-07-21 济南久隆医药科技有限公司 Preparation method of 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoro-ethanone
CN115959979A (en) * 2022-12-29 2023-04-14 南京正荣医药化学有限公司 Preparation method of 3-chloro-4-fluoro-5-trifluoromethyl trifluoroacetophenone
CN116535298B (en) * 2023-07-06 2023-09-22 研峰科技(北京)有限公司 Synthesis method of 3',5' -dichloro-2, 2-trifluoro acetophenone

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102477000A (en) * 2010-11-24 2012-05-30 沈阳药科大学 Method for synthesizing phenylethanolamines
CN102741222A (en) * 2009-10-27 2012-10-17 拜尔农作物科学股份公司 Halogenalkyl-substituted amides used as insecticides and acaricides
CN102993022A (en) * 2011-09-14 2013-03-27 上海工程技术大学 Preparation method of bromoaniline
CN105566089A (en) * 2008-04-09 2016-05-11 杜邦公司 Method for preparing 3-trifluoromethyl chalcones
CN112110790A (en) * 2020-09-28 2020-12-22 杭州臻挚生物科技有限公司 Preparation method of 3, 5-dihalo trifluorotoluene and 3 '-chloro-5' - (trifluoromethyl) phenyl trifluoroacetone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566089A (en) * 2008-04-09 2016-05-11 杜邦公司 Method for preparing 3-trifluoromethyl chalcones
CN102741222A (en) * 2009-10-27 2012-10-17 拜尔农作物科学股份公司 Halogenalkyl-substituted amides used as insecticides and acaricides
CN102477000A (en) * 2010-11-24 2012-05-30 沈阳药科大学 Method for synthesizing phenylethanolamines
CN102993022A (en) * 2011-09-14 2013-03-27 上海工程技术大学 Preparation method of bromoaniline
CN112110790A (en) * 2020-09-28 2020-12-22 杭州臻挚生物科技有限公司 Preparation method of 3, 5-dihalo trifluorotoluene and 3 '-chloro-5' - (trifluoromethyl) phenyl trifluoroacetone

Also Published As

Publication number Publication date
CN113636919A (en) 2021-11-12

Similar Documents

Publication Publication Date Title
CN113636919B (en) Method for synthesizing 3-chloro-5-trifluoromethyl trifluoroacetophenone
Maul et al. Benzotrifluoride and derivatives: useful solvents for organic synthesis and fluorous synthesis
US20100065416A1 (en) 6-chloro-2-trichloromethyl pyridine preparation method
CN106905104A (en) A kind of synthetic method of the fluoride trifluoro toluene of 2 bromine 5
DK154069B (en) RODENTICID ACTIVE DIPHENYLAMINE COMPOUNDS, PROCEDURES FOR REDUCING A STOCK OF ROTS AND MOUSE AND RODENTICID TO USE THE PROCEDURE
CN109369407A (en) The preparation method of o-nitrobenzyl bromide
DE3046512A1 (en) METHOD FOR COUPLING ANILINE AND PHENYL COMPOUNDS
CN112645894B (en) Method for preparing sulpirazole intermediate 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocarboxamidine hydrochloride
CN103288708B (en) The preparation method of 1- aryl -2- indolinone derivative
CN115594608A (en) Preparation method of chlorantraniliprole intermediate
CN101700998A (en) Method for preparing pendimethalin by aminating dimethyl dinitroanisole
DE2731259A1 (en) PROCESS FOR THE MANUFACTURING OF SUBSTITUTED BENZALDEHYDE
CN101250144A (en) Method for preparing 4-trifluoro methylthio benzoic acid
US5043489A (en) Method of preparing monohalogenated nitroalkanes
Shaw et al. An efficient synthesis of 3-hydroxy-3-trifluoromethyl phthalide
CN107400060A (en) A kind of synthetic method of the bromaniline of 2 chlorine 6
US3984487A (en) Preparation of petachloronitrobenzene
CN107915659B (en) Synthetic method of 3, 4-dichlorobenzonitrile
Henry The Reaction of Amines with N-Methyl-N-nitroso-N'-nitroguanidine
IE43614B1 (en) Diphenylamines
JP2004026832A (en) Method for producing 2-acetyl-2-chloro-gamma-butyrolactone by reacting 2-acetyl-gamma-butyrolactone salt with chloride in the presence of water
CN111087294A (en) Preparation method of high-purity prohexadione calcium
CN107602407A (en) A kind of synthetic method of the fluoroacetanilide of 2 bromine 4
US4845279A (en) Method of preparing 4-trifluoromethyl-2-nitrobenzoic acid and novel isomer
CN113214087B (en) Preparation method and application of 4-chloro-3, 5-dinitro-benzotrifluoride

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant