CN112300014B - Method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using microchannel reactor - Google Patents
Method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using microchannel reactor Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthesis application, and provides a method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor, which comprises the steps of synchronously adding 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone solution, fuming sulfuric acid and fuming nitric acid into a first microchannel reactor through a metering pump respectively, and heating for nitration reaction to obtain 4-chloro-2- (trifluoroacetyl) nitrobenzene; and adding the solution of the 4-chloro-2- (trifluoroacetyl) nitrobenzene and hydrogen into a micro mixer through a high-pressure constant flow pump and a gas flowmeter respectively to complete the mixing of gas and liquid phases to obtain a gas-liquid mixture, then adding the gas-liquid mixture into a second microchannel reactor with a catalyst loaded on the inner wall, and heating for hydrogenation reaction to obtain the 4-chloro-2- (trifluoroacetyl) aniline. The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention has the advantages of high purity of the obtained target product, stable temperature control and safe process, and is suitable for industrial popularization.
Description
Technical Field
The invention belongs to the technical field of organic synthesis application, and particularly relates to a method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor.
Background
The 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is a key intermediate of the anti-AIDS drug efavirenz, and a plurality of synthetic methods are reported in documents. For example, the literature Tetrahedron (1991, 3207), J.org.chem.63(23) (1998, 8536-8543), US5932726 and US05925789 report the synthesis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate starting from p-chloroaniline; chinese patent CN106496051 reports the synthesis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate using aniline as a starting material, all of which use n-butyllithium which is expensive and highly dangerous, and chinese patent CN102675125B reports that although n-butyllithium is not used in the preparation method, methyl trifluoropyruvate or ethyl ester is used in the reaction, which is more expensive than n-butyllithium.
The method reported in the Chinese patent CN106518636A relates to a two-step chemical high-risk hazardous process of nitration and hydrogenation, and has huge risk in production, although the used raw materials are easy to obtain and low in price.
As can be seen from the above published patent documents, the above processes are all batch reactor type processes, all use organic metal reagents or dangerous processes such as nitration, hydrogenation, etc., and have great risk in production.
Microchannel reactors generally refer to small reaction systems with feature sizes of 10 to 300 microns (or 1000 microns) fabricated by micromachining or precision machining techniques, and microreactor devices may be subdivided into micromixers, micro-heat exchangers, and microreactors depending on their primary use or function. Due to the internal microstructure, the micro-reactor equipment has extremely large specific surface area which can be hundreds of times or even thousands of times of the specific surface area of the stirring kettle. The micro-reactor has excellent heat transfer and mass transfer capacity, can realize instant uniform mixing of materials and efficient heat transfer, has a series of advantages of high safety, good operability and the like, and therefore, a plurality of reactions which cannot be realized in a conventional reactor can be realized in the micro-reactor.
Therefore, the invention utilizes the microchannel reactor to prepare the 4-chloro-2- (trifluoroacetyl) aniline, which is a breakthrough of the conventional kettle type preparation process.
Disclosure of Invention
The invention aims to solve the problem of high production risk and provide a method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor, wherein the production process is safe.
The invention provides a method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor, which is characterized by comprising the following steps of: step 1, synchronously adding a 2,2, 2-trifluoro- (3' -chlorphenyl) ethanone solution, fuming sulfuric acid and fuming nitric acid into a first microchannel reactor through a metering pump respectively, heating for nitration reaction to obtain a mixture of a 4-chloro-2- (trifluoroacetyl) nitrobenzene dichloromethane solution and mixed acid, and purifying the mixture to obtain 4-chloro-2- (trifluoroacetyl) nitrobenzene; step 2, adding the solution of 4-chloro-2- (trifluoroacetyl) nitrobenzene and hydrogen into a micro mixer through a high-pressure constant flow pump and a gas flow meter respectively to complete the mixing of gas and liquid phases to obtain a gas-liquid mixture, then adding the gas-liquid mixture into a second microchannel reactor, and heating for hydrogenation reaction to obtain 4-chloro-2- (trifluoroacetyl) aniline; wherein the inner wall of the second microchannel reactor is loaded with a catalyst.
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, in the step 1, the volume ratio of the 2,2, 2-trifluoro- (3' -chlorphenyl) ethanone solution to the fuming sulfuric acid to the fuming nitric acid is 4.62: 1.15: 2.3.
the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, the purification operation in the step 1 is as follows: and (3) pumping the mixture into a batch type reaction kettle for layering, washing the obtained organic layer with water, and concentrating to obtain the 4-chloro-2- (trifluoroacetyl) nitrobenzene.
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, the reaction temperature in the step 1 is controlled by an external heat exchanger, the heat exchange medium is water or heat transfer oil, and the temperature is 30-80 ℃.
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, the reaction temperature in the step 2 is controlled by an external heat exchanger, the heat exchange medium is water or heat transfer oil, and the temperature is 10-40 ℃.
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, the second microchannel reactor in the step 2 is a 304L stainless steel microchannel reactor.
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, the catalyst in the step 2 is Pd (NO) 3 ) 2 。
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, the first microchannel reactor in step 1 is a hastelloy microchannel reactor.
The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein, in the step 1, the solvent in the 2,2, 2-trifluoro- (3 '-chlorophenyl) ethanone solution is dichloromethane, and the mass ratio of the 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone to the dichloromethane is 8: 2.
the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention can also have the following characteristics: wherein the reaction time of the nitration reaction in the step 1 is 60 s-65 s, and the reaction time of the hydrogenation reaction in the step 2 is 10 s-30 s.
Action and Effect of the invention
According to the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor, 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone, fuming sulfuric acid and fuming nitric acid are used as starting raw materials, nitration reaction is carried out in a first microchannel reactor to prepare 4-chloro-2- (trifluoroacetyl) nitrobenzene, then the 4-chloro-2- (trifluoroacetyl) nitrobenzene is subjected to hydrogenation reduction in a second microchannel reactor with a wall carrying a catalyst to obtain the 4-chloro-2- (trifluoroacetyl) aniline, the total yield of target products is more than 88%, and the purity can reach 99.77% by GC detection.
In addition, the nitration reaction is a strong exothermic reaction, the reaction speed is high, the heat release is large, products or byproducts have explosion risks, the conventional batch type reaction kettle is easy to explode due to large reaction volume and poor heat transfer effect, and the microchannel reactor has small reaction liquid holdup, good heat transfer effect and no explosion risk.
In addition, the hydrogenation reaction is also a strong exothermic reaction, the temperature is not easy to control by using a conventional batch type reaction kettle, side reactions are more, the requirements on the pressure and the stirring speed of the reaction are higher, the reaction liquid holdup of the microchannel reactor is small, the heat transfer effect is good, the reaction temperature can be accurately controlled, and the reaction purity is high.
Therefore, the target product obtained by the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor provided by the invention has high purity, stable temperature control and safe process, and is suitable for industrial popularization.
Drawings
FIG. 1 is a gas phase detection spectrum of 4-chloro-2- (trifluoroacetyl) nitrobenzene in an example of the present invention; and
FIG. 2 is a gas phase detection spectrum of 4-chloro-2- (trifluoroacetyl) aniline in the example of the present invention.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor is specifically described below by combining the embodiment and the attached drawings.
The raw materials and reagents used in the following examples were purchased from conventional biochemical reagent stores, unless otherwise specified.
The reaction route of the invention is as follows:
the invention provides a method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor, which specifically comprises the following steps:
step 1, synchronously adding a 2,2, 2-trifluoro- (3' -chlorphenyl) ethanone solution, fuming sulfuric acid and fuming nitric acid into a first microchannel reactor through a metering pump respectively, heating for nitration reaction to obtain a mixture of a 4-chloro-2- (trifluoroacetyl) nitrobenzene dichloromethane solution and mixed acid, and purifying the mixture to obtain 4-chloro-2- (trifluoroacetyl) nitrobenzene;
and 2, adding the solution of the 4-chloro-2- (trifluoroacetyl) nitrobenzene and hydrogen into a micro mixer through a high-pressure constant flow pump and a gas flow meter respectively to complete the mixing of gas and liquid phases to obtain a gas-liquid mixture, then adding the gas-liquid mixture into a second microchannel reactor, and heating for hydrogenation reaction to obtain the 4-chloro-2- (trifluoroacetyl) aniline.
In the step 1, the solvent in the 2,2, 2-trifluoro- (3 '-chlorophenyl) ethanone solution is dichloromethane, and the mass ratio of the 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone to the dichloromethane is 8: the volume ratio of the 2,2,2, 2-trifluoro- (3' -chlorophenyl) ethanone solution to the fuming sulfuric acid to the fuming nitric acid is 4.62: 1.15: 2.3, the first microchannel reactor is a hastelloy microchannel reactor, the reaction temperature is controlled by an external heat exchanger, the heat exchange medium is water or heat transfer oil, the temperature is 30-80 ℃, and the reaction time of the nitration reaction is 60-65 s.
Further, the purification operation in step 1 is: and (3) pumping the mixture into an intermittent reaction kettle for layering, and washing and concentrating the obtained organic layer to obtain the 4-chloro-2- (trifluoroacetyl) nitrobenzene.
In addition, the reaction temperature in the step 2 is controlled by an external heat exchanger, the heat exchange medium is water or heat conduction oil, the temperature is 10-40 ℃, and the reaction time of the hydrogenation reaction is 10-30 s.
In addition, in step 2, the second microchannel reactor is a 304L stainless steel microchannel reactor, the inner wall of which carries a catalyst, and the catalyst is Pd (NO) 3 ) 2 With Al 2 O 3 Is a carrier.
< example >
Step 1, 4-chloro-2- (trifluoroacetyl) nitrobenzene preparation, the reaction equation is as follows:
the specific operation is as follows:
setting the temperature to 71 ℃ on an operation panel of the cold and hot all-in-one machine, and starting to heat up by clicking operation. The reaction temperature is controlled by an external heat exchanger, and the heat exchange medium is heat conduction oil. The feeding flow rates of the raw material liquid (2,2, 2-trifluoro- (3' -chlorophenyl) ethanone solution), fuming sulfuric acid and fuming nitric acid are respectively 4.62mL/min, 1.15mL/min and 2.3 mL/min. After the temperature of each micro-reaction plate displayed on the paperless recorder is stabilized at 71 ℃, starting a feeding pump for conveying the raw material liquid and fuming sulfuric acid, then starting a feeding pump for conveying nitric acid, starting feeding, and starting discharging after about 61 s. After the discharge is stable (generally about 3 min), collecting the feed liquid at the discharge outlet of the hastelloy micro-channel reactor into a washing kettle, standing for layering, separating an acid layer, washing an organic layer to be neutral by using a sodium carbonate aqueous solution, and concentrating under reduced pressure to obtain the 4-chloro-2- (trifluoroacetyl) nitrobenzene, wherein the purity of the nitrobenzene is 94.59% through gas phase (GC). And (3) discharging and weighing after detection, wherein the yield is 96.7%, and then adding methanol with the proportion amount for dissolving for later use. The results are shown in FIG. 1 and Table 1.
TABLE 14 GC data for chloro-2- (trifluoroacetyl) nitrobenzene
| Number of peak | Retention time (min) | Percentage of area |
| 1 | 2.108 | 0.616 |
| 2 | 3.545 | 0.052 |
| 3 | 10.747 | 1.405 |
| 4 | 13.693 | 0.057 |
| 5 | 13.931 | 0.316 |
| 6 | 14.047 | 94.591 |
| 7 | 14.464 | 2.907 |
| 8 | 14.991 | 0.057 |
FIG. 1 is a gas phase detection spectrum of 4-chloro-2- (trifluoroacetyl) nitrobenzene in the examples of the present invention.
As shown in fig. 1 and table 1, 8 peaks were obtained, and when compared with the retention time of the standard substance tested under the same conditions, the peak number was 6, and the peak having a retention time of 14.047min was the peak of 4-chloro-2- (trifluoroacetyl) nitrobenzene obtained in this example, and the purity of 4-chloro-2- (trifluoroacetyl) nitrobenzene was 94.59% by using the area normalization method.
Step 2, preparation of 4-chloro-2- (trifluoroacetyl) aniline, the reaction equation is as follows:
the specific operation is as follows:
(1) preparation of wall-supported catalyst: cleaning a stainless steel bottom plate of a 304L stainless steel microchannel reactor by using a detergent and deionized water, removing oil stains, and then cleaning Al 2 O 3 The glue is uniformly applied to the inner surface of the microchannel, dried at 90 deg.C and at 400 deg.CAnd (4) roasting. Then Pd (NO) is added by an equal volume impregnation method 3 ) 2 Solution impregnation to Al 2 O 3 Coating, drying at 90 deg.C, calcining at 400 deg.C, and coating with H 2 And N 2 Mixed gas (volume fraction is H) 2 10%) was reduced at 400 c for 2 hours and, after treatment, reloaded into a 304L stainless steel microchannel reactor.
(2) Reaction operation: setting the temperature to be 35 ℃ on an operation panel of the cold-hot all-in-one machine, and starting heating by clicking operation. The reaction temperature is controlled by an external heat exchanger, and the heat exchange medium is water. Setting a feeding flow rate of 10mL/min for 4-chloro-2- (trifluoroacetyl) nitrobenzol solution on a feeding pump panel, starting a feeding pump and a hydrogen valve for the 4-chloro-2- (trifluoroacetyl) nitrobenzol solution after the temperature of each micro-anti-reaction plate displayed on a paperless recorder is stabilized at 35 ℃, keeping the retention time of the feed liquid in a micro-channel for about 20s, collecting the feed liquid at the outlet of a 304L stainless steel micro-channel reactor, concentrating under reduced pressure to a certain degree, cooling for crystallization, filtering, drying to obtain 4-chloro-2- (trifluoroacetyl) aniline, detecting the purity to be 99.77% by gas phase (GC), weighing, and calculating the yield to be 91.2% by using 4-chloro-2- (trifluoroacetyl) nitrobenzene. The results are shown in FIG. 2 and Table 2.
TABLE 24 GC data for chloro-2- (trifluoroacetyl) aniline
| Number of peak | Retention time (min) | Percentage of area |
| 1 | 1.042 | 0.034 |
| 2 | 1.233 | 0.007 |
| 3 | 1.661 | 99.770 |
| 4 | 1.819 | 0.017 |
| 5 | 1.983 | 0.029 |
| 6 | 2.113 | 0.006 |
| 7 | 2.223 | 0.003 |
| 8 | 4.456 | 0.063 |
| 9 | 4.631 | 0.007 |
| 10 | 4.657 | 0.029 |
| 11 | 5.149 | 0.010 |
| 12 | 5.525 | 0.005 |
| 13 | 7.273 | 0.020 |
FIG. 2 is a gas phase detection spectrum of 4-chloro-2- (trifluoroacetyl) aniline in the example of the present invention.
As shown in fig. 2 and table 2, 13 peaks were obtained, and when compared with the retention time of the standard product measured under the same conditions, the peak number was 3, the peak having a retention time of 1.667min was the peak of 4-chloro-2- (trifluoroacetyl) aniline produced in this example, and the purity of 4-chloro-2- (trifluoroacetyl) aniline was 99.77% by area normalization.
Effects and effects of the embodiments
According to the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using the microchannel reactor, provided by the embodiment of the invention, 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone, fuming sulfuric acid and fuming nitric acid are used as starting materials, nitration reaction is carried out in a Hastelloy microchannel reactor to prepare 4-chloro-2- (trifluoroacetyl) nitrobenzene, then the 4-chloro-2- (trifluoroacetyl) nitrobenzene is subjected to hydrogenation reduction in a 304L stainless steel microchannel reactor with a catalyst loaded on the wall to obtain the 4-chloro-2- (trifluoroacetyl) aniline, the total yield of target products is more than 88%, and the purity can reach 99.77% by GC detection.
In addition, the nitration reaction is a strong exothermic reaction, the reaction speed is high, the exothermic amount is large, the product or by-product has explosion danger, the conventional batch type reaction kettle is easy to explode due to large reaction volume and poor heat transfer effect, and the microchannel reactor has small reaction liquid holdup, good heat transfer effect and no explosion risk.
In addition, the hydrogenation reaction is also a strong exothermic reaction, the temperature is not easy to control by using a conventional batch type reaction kettle, side reactions are more, the requirements on the pressure and the stirring speed of the reaction are higher, the reaction liquid holdup of the microchannel reactor is small, the heat transfer effect is good, the reaction temperature can be accurately controlled, and the reaction purity is high.
In addition, the single treatment capacity of the improved 304L stainless steel microchannel reactor is far greater than that of the existing microchannel reactor, so that the method is beneficial to mass production and has the significance of industrial popularization.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (7)
1. A method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline by using a microchannel reactor is characterized by comprising the following steps of:
step 1, synchronously adding a 2,2, 2-trifluoro- (3' -chlorphenyl) ethanone solution, fuming sulfuric acid and fuming nitric acid into a first microchannel reactor through a metering pump respectively, heating for nitration reaction to obtain a mixture of a 4-chloro-2- (trifluoroacetyl) nitrobenzene dichloromethane solution and mixed acid, and purifying the mixture to obtain 4-chloro-2- (trifluoroacetyl) nitrobenzene;
step 2, adding the solution of the 4-chloro-2- (trifluoroacetyl) nitrobenzene and hydrogen into a micro mixer through a high-pressure constant flow pump and a gas flow meter respectively to complete the mixing of gas and liquid phases to obtain a gas-liquid mixture, then adding the gas-liquid mixture into a second microchannel reactor, heating for hydrogenation reaction to obtain 4-chloro-2- (trifluoroacetyl) aniline,
wherein, the first microchannel reactor in the step 1 is a hastelloy microchannel reactor,
in the step 2, a catalyst is loaded on the inner wall of the second microchannel reactor, and the catalyst is Pd (NO) 3 ) 2 And the second microchannel reactor is a modified 304L stainless steel microchannel reactor.
2. The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline using a microchannel reactor as claimed in claim 1, wherein:
wherein the volume ratio of the 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone solution, the oleum and the oleum in the step 1 is 4.62: 1.15: 2.3.
3. the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline using a microchannel reactor as claimed in claim 1, wherein:
wherein the purification operation in the step 1 is as follows: and (3) pumping the mixture into a batch type reaction kettle for layering, and washing and concentrating the obtained organic layer to obtain the 4-chloro-2- (trifluoroacetyl) nitrobenzene.
4. The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline using a microchannel reactor as claimed in claim 1, wherein:
wherein, the reaction temperature in the step 1 is controlled by an external heat exchanger, the heat exchange medium is water or heat transfer oil, and the temperature is 30-80 ℃.
5. The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline using a microchannel reactor as claimed in claim 1, wherein:
wherein, the reaction temperature in the step 2 is controlled by an external heat exchanger, the heat exchange medium is water or heat transfer oil, and the temperature is 10-40 ℃.
6. The method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline using a microchannel reactor as claimed in claim 1, wherein:
wherein, the solvent in the 2,2, 2-trifluoro- (3 '-chlorophenyl) ethanone solution in the step 1 is dichloromethane, and the mass ratio of the 2,2, 2-trifluoro- (3' -chlorophenyl) ethanone to the dichloromethane is 8: 2.
7. the method for synthesizing 4-chloro-2- (trifluoroacetyl) aniline using a microchannel reactor as claimed in claim 1, wherein:
wherein the reaction time of the nitration reaction in the step 1 is 60 s-65 s,
the reaction time of the hydrogenation reaction in the step 2 is 10-30 s.
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|---|---|---|---|---|
| US20110015189A1 (en) * | 2009-07-20 | 2011-01-20 | Apotex Pharmachem Inc. | Methods of making efavirenz and intermediates thereof |
| CN103113235A (en) * | 2012-10-15 | 2013-05-22 | 常州大学 | Method for synthesizing nitryl chloroaniline compound by using micro-channel reactor |
| CN106518636A (en) * | 2016-10-18 | 2017-03-22 | 浙江天宇药业股份有限公司 | Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof |
| CN108191670A (en) * | 2018-01-05 | 2018-06-22 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of the micro passage reaction synthesis chloro- 3- 5-trifluoromethylanilines of 4- |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110015189A1 (en) * | 2009-07-20 | 2011-01-20 | Apotex Pharmachem Inc. | Methods of making efavirenz and intermediates thereof |
| CN103113235A (en) * | 2012-10-15 | 2013-05-22 | 常州大学 | Method for synthesizing nitryl chloroaniline compound by using micro-channel reactor |
| CN106518636A (en) * | 2016-10-18 | 2017-03-22 | 浙江天宇药业股份有限公司 | Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof |
| CN108191670A (en) * | 2018-01-05 | 2018-06-22 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of the micro passage reaction synthesis chloro- 3- 5-trifluoromethylanilines of 4- |
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