Process for producing 2-fluoro-4-(trifluoromethyl) acetanilide

Disclosed is a process for producing 2-fluoro-4-(trifluoromethyl) acetanilide which comprises reacting 3,4-difluorobenzotrifluoride with acetamide in the presence of a base in an aprotic polar solvent or in a mixture of an aprotic polar solvent and an aprotic non-polar solvent.

FIELD OF THE INVENTION 
This invention relates to an industrially advantageous process for 
producing 2-fluoro-4-(trifluoromethyl)acetanilide, which is useful as an 
intermediate for the production of insecticides. 
BACKGROUND OF THE INVENTION 
The so-far known processes for producing 
2-fluoro-4(trifluoromethyl)acetanilide as described in J. Org. Chem., 50, 
4576 (1985) and EP-A-0246061 may be illustrated as follows: 
##STR1## 
However, these processes are not necessarily satisfactory for the 
commercial production of 2-fluoro-4(trifluoromethyl)acetanilide. That is 
to say, trifluoromethyl hypofluorite is hardly available because of the 
necessity of special fluorine-handling techniques, while xenon difluoride 
is an expensive reagent and the fluorination therewith is not very 
regioselective, hence the purity of the product is not good. Furthermore, 
these processes give only low yields and cannot be said to be advantageous 
from the commercial standpoint, 
SUMMARY AND DESCRIPTION OF THE INVENTION 
Under the circumstances, we made intensive investigations in an attempt to 
develop a process for producing 2-fluoro-4-(trifluoromethyl)acetanilide 
which is much improved from the industrial viewpoint. As a result, we 
found that the object can be achieved when the method mentioned below is 
used. Based on this finding, we have completed the present invention. 
The invention thus provides a process for producing 
2-fluoro-4-(trifluoromethyl)acetanilide which comprises reacting 
3,4-difluorobenzotrifluoride with acetamide in the presence of a base in 
an aprotic polar solvent or in a mixture of an aprotic polar solvent and 
an aprotic non-polar solvent. 
As for the amounts of the reactants, acetamide and the base are each used 
generally in an amount of about 1 to about 10 moles, preferably (from the 
viewpoint of the reaction yield and the economics) about 1.8 to about 2.2 
moles, per mole of 3,4-difluorobenzotrifluoride. The reaction is carried 
out at a temperature within the range of usually about 30.degree. to about 
160.degree. C., preferably about 40.degree. to about 100.degree. C., 
usually for a period of about 0.5 to about 100 hours. 
The base includes a non-nucleophilic strong base, for example, an alkali 
metal hydride such as sodium hydride, or an alkali metal carbonate such as 
potassium carbonate. 
The aprotic polar solvent includes, among others, dimethylformamide, 
dimethyl sulfoxide, hexamethylphosphoric triamide, sulfolane, 
N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, 
1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidone, acetonitrile, 
tetrahydrofuran and dioxane, and mixtures of these. 
Furthermore, as a solvent, a mixture of an aprotic polar solvent and an 
aprotic non-polar solvent may also be used. The aprotic non-polar solvent 
is preferably, for example, an aromatic hydrocarbon (e.g. C.sub.6 
-C.sub.8) such as benzene, toluene, etc., an aliphatic hydrocarbon (e.g. 
C.sub.6 -C.sub.8) such as hexane, heptane etc., or a halogenated 
hydrocarbon (e.g. C.sub.1 -C.sub.6) solvent such as chloroform, carbon 
tetrachloride, chlorobenzene, etc, and mixture of these. When such mixture 
of an aprotic polar solvent and an aprotic non-polar solvent is used as 
the reaction solvent, the amount of the aprotic polar solvent is 
preferably more than 50 wt.% based on the weight of said mixture. 
In order to isolate the desired product, namely 
2-fluoro-4-(trifluoromethyl) acetanilide, the reaction mixture is first 
treatd with water or a diluted acid, such as aqueous hydrochloric acid, 
aqueous ammonium chloride, aqueous citric acid and then subjected to 
organic solvent extraction and concentration. Examples of organic solvent 
useful for the extraction is diethyl ether, diisopropyl ether, 
dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, 
xylene, chlorobenzene, bromobenzene, ethyl acetate, n-hexane or n-heptane. 
If necessary, the desired product 2-fluoro-4(trifluoromethyl)acetanilide 
can further be purified by recrystallization or chromatography, for 
instance. 
If desired, unreacted 3,4-difluorobenzotrifluoride can be recovered from 
the reaction mixture by distillation or by organic solvent extraction 
followed by distillation. If the reaction mentioned above is carried out 
in a reactor equipped with a distillation apparatus, the unreacted 
3,4-difluorobenzotrifluoride can directly be recovered by distillation of 
the reaction mixture. For conducting the organic solvent extraction, the 
reaction mixture is treated with water or a diluted acid such as aqueous 
hydrochloric acid, and then subjected to extraction using a low-boiling 
organic solvent such as diethyl ether, dichloromethane, n-hexane etc. 
After separation of the aqueous layer, the organic layer is distilled, 
whereby the unreacted 3,4-difluorobenzotrifluoride is recovered. As a 
result, the desired product, 2-fluoro-4-(trifluoromethyl) acetoanilide is 
also obtained as a residue. 
The desired product 2-fluoro-4-(trifluoromethyl) acetanilide can be 
converted, upon hydrolysis (deacetylation), to 
4-amino-3-fluorobenzotrifluoride, which in turn is converted to 
benzoylurea insecticides, as described, for instance, in EP-A-0246061. The 
conversion of 2-fluoro-4-(trifluoromethyl)acetanilide to 
4-amino-3-fluorobenzotrifluoride by hydrolysis is also described in detail 
in Reference Example 1 to be set forth later. 
The starting material for carrying out the process of the invention, namely 
3,4-difluorobenzotrifluoride, can be prepared, for instance, by the method 
described in U.S. Pat. No. 4,937,396. 
The following working examples and reference example are further 
illustrative of the present invention but are by no means limitative of 
the scope thereof.

EXAMPLE 1 
A reactor was charged with 13.6 g (0.231 mole) of acetamide, 9.23 g of 
sodium hydride (60% w/w dispersion in mineral oil, 0.23 mole) and 200 ml 
of dimethylformamide, and the mixture was heated to 60.degree. C. with 
stirring At that temperature, a solution of 20 g (0.11 mole) of 
3,4-difluorobenzotrifluoride in 20 ml of dimethylformamide was added 
dropwise gradually to the reactor contents After completion of the 
dropwise addition, the reactor contents were heated to 100.degree. C. and 
further stirred for an hour. 
The reaction mixture was cooled to room temperature (about 20.degree. C.) 
and then poured slowly into 5% hydrochloric acid, and the resultant 
mixture was extracted with two 300-ml portions of ethyl acetate. The ethyl 
acetate layers were combined, washed with water, dried over anhydrous 
sodium sulfate and concentrated to give a crude product. This crude 
product was subjected to silica gel column chromatography (eluent: 
n-hexane/ethyl acetate =1/1) to give 18.7 g of 
2-fluoro-4-(trifluoromethyl) acetanilide. 
Yield 77%. Melting point 135.6.degree. C. 
EXAMPLE b 2 
A reactor was charged with 0.32 g (5.42 mmoles) of acetamide, 0.22 g of 
sodium hydride (60% w/w disperision in mineral oil, 5.5 mmoles), 0.5 g 
(2.75 mmoles) of 3,4difluorobenzotrifluoride and 10 ml of dimethyl 
sulfoxide, and the mixture was heated to 60.degree. C. with gentle 
stirring. Then, after stirring at 60-65.degree. C. for 30 minutes, the 
reaction mixture was cooled to room temperature (about 20.degree. C.) and 
slowly poured into 5% hydrochloric acid. The resultant mixture was 
extracted with two 200-ml portions of ethyl acetate. The ethyl acetate 
layers were combined, washed with water, dried over anhydrous magnesium 
sulfate and concentrated to give a crude product. This crude product was 
subjected to silica gel column chromatography (eluent: n-hexane/ethyl 
acetate =1/1) to give 0.45 g of 2-fluoro-4-(trifluoromethyl) acetanilide. 
Yield 95%. Melting point 135.4.degree. C. 
REFERENCE EXAMPLE 1 
A reactor was charged with 10.0 g of 
2-fluoro-4(trifluoromethyl)acetanilide, 50 ml of 20% aqueous sulfuric acid 
and 50 ml of methyl alcohol, and the mixture was stirred under reflux for 
4 hours. The reaction mixture was cooled to room temperature (about 
20.degree. C.) and then made weakly alkaline by slowly adding a 5% aqueous 
solution of sodium hydrogen carbonate. The resultant solution was then 
extracted with two 200-ml portions of diethyl ether. The diethyl ether 
layers were combined, washed with water, dried over anhydrous magnesium 
sulfate and concentrated to give a crude product. This crude product was 
subjected to silica gel column chromatolography (eluent: n-hexane/ethyl 
acetate = 4/1 ) to give 7.29 g of 4-amino-3-fluorobenzotrifluoride. 
Yield 90%. Refractive index n.sub.D.sup.22.5 =1.4642. 
As a process for producing 2-fluoro-4-(trifluoromethyl)acetanilide, the 
process of the invention is advantageous over the prior art methods from 
the industrial standpoint since the desired product can be obtained with 
high selectivity and high yield by reacting 3,4-difluorobenzotrifluoride 
with acetamide which is inexpensive.