JPH0441466A - Production of difluoroaniline - Google Patents

Abstract

PURPOSE:To industrially advantageously obtain the subject compound from a readily available and tractable raw material by subjecting 5-chloro-2,4,6- trifluoroisophthalic acid to decarbonic acid reaction, dechlorination reaction and substituting reaction of fluorine atom to amino group, in turn. CONSTITUTION:5-chloro-2,4,6-trifluoroisophthalic acid is subjected to decarbonic acid reaction by heating at 110-350 deg.C, preferably 120-180 deg.C in a non-protonic polar solvent to obtain 1-chloro-2,4,6-trifluorobenzene. Next, said compound is subjected to heating treatment in the presence of metal and water under pressurized condition to generate 1,3,5-trifluorobenzene and said compound is reacted with aminating agent (e.g., ammonia or metallic amide salt) in a polar solvent at a temperature of 100-300 deg.C to substitute a fluorine atom to amino group to afford 3,5-difluoroaniline extremely useful as an intermediate of medical drug, agricultural chemical and industrial agent, etc.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is applicable to intermediates for pharmaceuticals, agricultural chemicals, industrial chemicals, etc.
The present invention relates to a very useful method for producing 3,5-difluoroaniline.

[Conventional technology and its problems]

Conventionally, regarding 3,5-difluoroaniline, Finger et al.'s 2,4-difluoroaniline was used as a starting material and 5
A method of synthesis through steps (J, Am.

Chew, Soc, 73.153 (1951)
) and 1.3.5- ) dichloro-2,4,8 of Ishikawa et al.
- Method using trifluorobenzene as a starting material [Japanese Chemical Journal 87゜1089 (196B), same magazine 86.120
2 (1965)) is known.

However, the former method required extremely multi-step reactions including the synthesis of 2,4 difluoroaniline as a starting material, and the yield was poor. In addition, in the latter method, hexachlorobenzene, which is necessary for the synthesis of the starting material 1,3.5-)lichloro-2.4.8-)lifluorobenzene, is
It is designated as a Class 1 Specified Chemical Substance under the Act on the Examination and Regulation of Manufacturing, etc. of Chemical Substances (commonly known as the Chemical Substances Control Law), and there have been problems with its acquisition and handling.

[Purpose of the invention]

The present invention aims to solve the problems associated with the prior art as described above, and aims to provide a new and industrially advantageous manufacturing method for 3,5-difluoroaniline. .

Means for Solving Problems c] The present invention decarboxylates 5-chloro-2,4,6-trifluoroisophthalic acid to produce 1-chloro-2,
4,6-trifluorobenzene is produced, and then the 1
-Chloro-2,4J-1-lifluorobenzene is subjected to a dechlorination reaction to produce 1.3.5-trifluorobenzene, and then one unit of the 1.3.5-trifluorobenzene is The present invention relates to a method for producing difluoroaniline, characterized in that 3,5-difluoroaniline is produced by substituting a fluorine atom with an amino group.

That is, the present invention is a method for producing 3,5-difluoroaniline by reacting 5-chloro-2,4-rotrifluoroisophthalic acid in the following three steps. This will be explained in detail below.

The first reaction is to decarboxylate 5-chloro-2,4,[i-trifluoroisophthalic acid to produce 1-chloro-
This is a reaction that produces 2,4,B-trifluorobenzene. The decarboxylation reaction can be performed by applying a conventionally known reaction, and is a reaction in which 5-chloro-2,4, rhotrifluoroisophthalic acid is heat-treated in a polar solvent.

As reaction solvent preferably water or an aprotic polar solvent is used. Examples of aprotic polar solvents include dimethylsulfoxide, dimethylformamide, N-
Methyl-2-pyrrolidone, benzonitrile, quinoline,
Examples include pyridine, sulfolane, and hexamethylphosphoramide.

The reaction temperature is generally 110 to 350°C,
Although it changes depending on the type of reaction solvent, a range of 120 to 180°C is preferable.

The reaction time is until the generation of carbon dioxide gas is finished, but is generally in the range of 0.1 to IO hours, preferably 0.3 to 8 hours.
It's time.

The amount of the solvent is preferably in the range of 1 to 100 times the weight of 1-chloro-2,4,6-trifluoroisophthalic acid.

If the reaction solvent is removed and precision distillation is performed, 1-chloro-2
, 4, lotrifluorobenzene can be isolated.

The second reaction is a reaction in which 1,3,5-trifluorobenzene is produced by dechlorinating 1-chloro-2,4,B-trifluorobenzene. The dechlorination reaction is preferably a reaction in which 1-chloro-2,4,8-trifluorobenzene is heat-treated under pressure conditions in the presence of a metal and water.

Since this reaction is a high temperature reaction, an autoclave is used. Examples of metals used include copper powder, Raney alloy, or zinc.
Copper couples are available, but copper powder and zinc-copper couples are preferred. The amount of water used is 1-chloro-2,4,8
It is preferably 0.5 to 2 times the mole of -1-lifluorobenzene. The reaction temperature is preferably 300 to 400°C, and the reaction time is 1 to 48 hours, although it is influenced by the reaction temperature and stirring efficiency. After the reaction, 1.3.5-1-lifluorobenzene can be isolated by distilling the reaction mixture under normal pressure.

The third reaction is a reaction in which 3,5-difluoroaniline is produced from 1,3,5-trifluorobenzene by substituting one fluorine atom with an amino group. The substitution reaction is preferably 1.3.57
) This is a reaction in which refluorobenzene is heat-treated with an aminating agent in a polar solvent.

Examples of aminating agents include ammonia, aqueous ammonia,
Metal amide salts can be used.

Examples of metal amide salts include sodium amide, potassium amide, and lithium amide.

Polar solvents capable of dissolving the aminating agent are suitable as solvents, among which acetonitrile and methanol are particularly suitable for isolation of the product. The amount of the aminating agent is preferably in the range of 1 to 100 times the amount of 1,3.5-trifluorobenzene, although it depends on the type of the aminating agent. The reaction temperature is preferably 100 to 300°C, and the reaction time using an autoclave as the reaction vessel varies depending on the type of aminating agent, but is preferably in the range of 2 to 96 hours. After the reaction, isolation is preferably performed by steam distillation.

In the present invention, the products of the first reaction and the second reaction can be used in the next step of reaction without being isolated and purified, but it is preferable to isolate and purify them.

In addition, 5-chloro-2,4,6 used as a starting material in the method for producing 3,5-difluoroaniline of the present invention.
-Trifluoroisophthalic acid can be obtained from tetrachloroisophthalonitrile, which is the active ingredient of the commercially available agricultural and horticultural fungicide Daconyl [F], by a known method [Kagaku Kogyo Zasshi 73, 447 (1970)]. Therefore, it is easy to obtain and handle.

[Example-1] (First reaction = 1-chloro2.4,6
-Production method of trifluorobenzene) 60 g of 5-chloro-2,4,6-1-lifluoroisophthalic acid was added to 90 ml of N,N-dimethylformamide and heated and stirred in an oil bath at 150°C. Carbon dioxide gas begins to be generated, and then the target product, 1-chloro2.4.6-trifluorobenzene, is distilled out, which is cooled and collected in a Liebig condenser.

After about 1 hour, after the generation of carbon dioxide gas has finished, heating is continued until the distillation of oil stops. The distillate was washed with water, and the oil layer was dried over sodium sulfate to obtain 36.1 g (yield: 92%) of 1-chloro2.4.8-)lifluorobenzene crude product.

19FNMR (CD0g3/C6F6) 51.98pp
IIl (m, 2F), 52.66 ppm (In, I
P)+f Part of the crude product is rectified to give a boiling point of 121-123
℃ (literature value 124 ℃) was obtained.

[Example-2] (Second reaction: Method for producing 1,3.54-trifluorobenzene) 1-chloro-2,4,6-trifluorobenzene66.
8g of copper powder, 5g of water, and 65g of copper powder were placed in an autoclave and heated to 300°C for 28 hours with high speed stirring. After the reaction, the contents were distilled off, the fractions at 74-77°C were collected, dried over sodium sulfate, and 1.3.5-trifluorobenzene 3
8.5 g (yield 73%) was obtained.

'HNMR (CDCN 3/TMS) 6.61ppa+(+a) 19F NMR (CDCp3106F6) 54.6pp
m(II) [Example-3] (Second reaction: 1.3.5-trifluorobenzene manufacturing method) 1-chloro-2,4,6-trifluorobenzene 6.6
8g 1 water 0.5g and zinc-copper couple (add a copper sulfate aqueous solution with a metal atomic ratio of 3 to 5% to the zinc powder-water suspension and leave it to stand, then remove the solid matter under reduced pressure, wash with water, and dry. 7.5z (finely ground in a mortar) was placed in an autoclave and heated to 330°C for 32 hours with high speed stirring.

After the reaction, the contents were distilled off, and the fractions at 74 to 77°C were collected and dried over sodium sulfate to obtain 2.19 g (yield: 42%) of 1,3,5-trifluorobenzene.

[Example-4] (Third reaction = manufacturing method of 3.5-difluoroaniline) 1.3.5 26.5 g of -1-lifluorobenzene,
Ammonia gas is sealed in a Teflon sealed container with 200 ml of methyl alcohol saturated at room temperature,
Heated on an oil bath set at 200°C. The reaction was stopped after 60 hours. After the reaction, remove the solvent and unreacted 1 under reduced pressure.
．． 3.5-) Lifluorobenzene is distilled off and the mixture of the remaining solid and oily substance is extracted with ether to form an oily substance 24.8
(The yield of 3,5-difluoroaniline is 93% by GLC analysis.)

The HNMR, 19F NMR of this oil is as follows: That's right.

'HNMR (CDCR3/TMS) 4.16ppm (br, 2tl), 6.01ppm (
II, IH) 6.27 ppm (s, IH) 'F NMR (CDCN 3/C6F6) 51, O7
ppm, 51.14 ppmFurthermore, this oily substance was rectified to give a boiling point of 80°C/20mm/g and a melting point of 39-40
3.5-difluoroaniline was obtained.

[Example-5] (Third reaction: method for producing 3,5-difluoroaniline) 9.6 g of sodium amide instead of ammonia.

Using acetonitrile instead of methyl alcohol,
A reaction similar to Example 4 was conducted. 3 by GLC analysis
．． The yield of 5-difluoroaniline was 51%.

Claims (4)

[Claims] (1) By decarboxylating 5-chloro-2,4,6-trifluoroisophthalic acid, 1-chloro-2,4
, 6-trifluorobenzene, and then the 1-
By subjecting chloro-2,4,6-trifluorobenzene to a dechlorination reaction, 1,3,5-trifluorobenzene is produced, and then one fluorine in the 1,3,5-trifluorobenzene is A method for producing difluoroaniline, which comprises producing 3,5-difluoroaniline by substituting an atom into an amino group. (2) The method for producing difluoroaniline according to claim 1, wherein the decarboxylation reaction is a reaction in which 5-chloro-2,4,6-trifluoroisophthalic acid is heat-treated in an aprotic polar solvent. (3) The method for producing difluoroaniline according to claim 1, wherein the dechlorination reaction is a reaction in which 1-chloro-2,4,6-trifluorobenzene is heat-treated under pressurized conditions in the presence of a metal and water. (4) The reaction of replacing one fluorine atom of 1,3,5-trifluorobenzene with an amino group is amination, in which 1,3,5-trifluorobenzene is heat-treated with an aminating agent in a polar solvent. The manufacturing method according to claim 1, 2, or 3, which is a reaction.