JPH0334944A - Production of m-halofluorobenzene - Google Patents

Abstract

PURPOSE:To obtain the subject compound in high yield by carrying out dediazoniating reductive reaction of a relatively inexpensive 2,4-or 2,6- halofluoroaniline at a specific temperature using hypophosphoric acids as a reducing agent and passing the resultant compound through ordinary diazotizing reaction. CONSTITUTION:(a) A 2,4- or 2,6-halofluoroaniline, especially 2,4- or 2,6- difluoroaniline (raw material) is diazotized to provide a diazonium salt. Hypo phosphoric acid or a salt thereof is then dripped into the resultant diazonium salt to carry out dediazoniating reduction or (b) the aforementioned raw material is subjected to diazotization-dediazoniating reduction in the presence of the hypophosphoric acid or salt thereof. Alternatively, (c) an aqueous solution of the hypophosphoric acid is added to the above-mentioned raw material to from a hypophosphite, which is then subjected to the diazotization-dediazoniating reduction to advantageously afford an m-halofluorobezene, especially m- difluorobenzene useful as an intermediate in the fine chemical field, such as fluorine-containing medicines, agricultural chemicals and liquid crystals.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel method for producing m-halofluorobenzene.

[Prior art and its problems]

m-Halofluorobenzene is usually produced by the dediazofluorination method of m-haloaniline (Balz-3chiemann
method). That is, m-haloaniline is diazotized, HBF4 is added thereto, and the resulting diazonium B
After the F4-salt is isolated and purified, it is thermally decomposed to obtain m-halofluorobenzene. However, the above-mentioned thermal decomposition requires a relatively high temperature, and since the reaction proceeds in a chain manner, it is difficult to control, and the reaction may be explosive. Yields are also generally low.

Also, aromatic amines at dry ice/acetone temperature)
A method is also known in which IF-organic base and NaNO2 are added to obtain aryldiazonium fluoride, which is then thermally decomposed at around 100°C. When this method is used, m-difluorobenzene can be obtained with a yield of nearly 80%, but the production volume per unit volume is low and it is not industrially practical, as a large amount of AHF (anhydrous hydrofluoric acid) is used.

[Knowledge about problem solving]

The present inventor carried out dediazo reduction at 0 to 30°C using hypophosphorous acid or its salt as a reducing agent, thereby achieving
M-
It was found that it was converted to halofluorobenzene.

[Structure of the invention]

Therefore, the present invention provides m-diazo reduction of 2,4- or 2,6-halofluoro-3-loaniline in the presence of hypophosphorous acid or a salt thereof, preferably at 0 to 30°C. A method for producing difluorobenzene is provided. Here, the term 2,4- or 2,6-halofluoroaniline means 2-fluoro-4-halofluoroaniline,
4-fluoro-2-haloaniline or 2-fluoro-
shall mean 6-haloaniline.

In addition, the present invention diazotizes 2,4- or 2,6-halofluoroaniline, and adds an aqueous solution of hypophosphorous acid or its salt dropwise to the resulting diazonilla 11 salt preferably at 0 to 30°C. A method for producing m-halofluorobenzene is provided, which comprises dediazo reduction of a salt.

Moreover, the present invention adds an aqueous solution of hypophosphorous acid to 2,4- or 2,6-halofluoroaniline to form a hypophosphite, and then preferably cools the hypophosphite at 0 to 30°C. Diazotization - A method for producing m-halofluorobenzene comprising diazo reduction is provided.

m-Halofluorobenzene is useful as a synthetic intermediate in the field of fine chemistry, such as fluorine-containing drugs, agricultural chemicals, and liquid crystals.

2,4- or 2,6-halofluoroaniline, which is a raw material for m-halofluorobenzene, is obtained by fluorinating 0- or P-chloronitrobenzene by a nucleophilic substitution reaction with a known alkali fluoride, and replacing the nitro group with a known alkali fluoride. After reduction by the method (and optionally acetylated amino groups) -N
HCOCH3) and halogenation. (
-N) In the case of ICOCH3, further hydrolysis is performed. ) 2,4-difluoroaniline and 2,6-difluoroaniline, which are raw materials for m-difluorobenzene, are obtained by converting 2,4- and 2,6-cyclonitrobenzene, respectively, into fluorine by a nucleophilic substitution reaction with a known alkali fluoride. and further reduce the nitro group by a known method.

Diazotization is generally carried out by conventional methods. That is, 2゜4- or 2,6-halofluoroaniline is dissolved in hydrochloric acid with a molar ratio of 2 times or more, preferably 2.5 to 4 times, and the resulting hydrochloride solution is added to water in an amount equal to or more than the same weight as aniline. Dilute with Dilution with water lowers the concentration of the solution and prevents foaming due to N2 gas generated during dediazotization and reduction. This is added to approximately the same mole as the aniline (about 1 to 2 times the molar ratio, preferably 1 to 2 times the molar ratio, preferably 1
．． 05-1.2 times) of NaN0□ is added as an aqueous solution. Alkyl nitrite may be used instead of thorium nitrite. When diazotization is performed before adding hypophosphorous acid or its salt, the reaction solution is -5 to 10
The diazotization reaction is completed by keeping the temperature preferably at 0-5°C.

Hypophosphorous acid or a salt thereof may be added before or after diazotization. Hypophosphorous acid or its salt is 2.4-
Alternatively, use approximately the same mole or more (approximately 1.2 to 1.5 times in molar ratio) as 2,6-halofluoroaniline, and after addition, the reaction solution is preferably kept at 50°C or below until dediazotization is completed. is maintained at 30°C or lower, more preferably 20°C or lower.

When diazotization is performed after addition of hypophosphorous acid or a salt thereof, dediazo reduction proceeds simultaneously with the production of diazonilla 11 salt. Therefore, the time required to pass through the unstable diazonium salt is shortened, and operability and reaction control are facilitated.

The produced llm-halofluorobenzene is isolated and purified by a commonly used method.

[Specific disclosure of the invention]

Loss Aim 1: Add 156.4 g (1.5 mol) of 35% hydrochloric acid to a four-eye flask equipped with a stirrer, reflux condenser, thermometer, and dropping funnel.
and 64.5 g of 2,7I-difluoroaniline (
0.5 mol) was added to prepare 2,4-difluoroaniline hydrochloride. Furthermore, add 100 mfl of water to dilute it.
Cooled to -1.0°C. After that, sodium nitrite 35.2
g (0,525 mol) in 73 g of water, 0 to 10
The mixture was added dropwise while maintaining the temperature at ℃ to complete diazotization. Furthermore, 50%-〇, 79.2 g of PO2 aqueous solution (0.6 mo
1) was added dropwise while maintaining a temperature of 0 to 30°C to carry out de-diazo reduction. After the generation of N2 has stopped, the liquid is separated by standing and washed sequentially with saline, 5%-Na)lcO3 aqueous solution, and saline.
After drying with MgSO4, the desired product was obtained by distillation. The yield of m-difluorobenzene was 77.2% (44.0 g).

Lost team 1 50%-11, 50 instead of PO2 aqueous solution 79.2E
%-N a H2P O.

The same procedure as above was carried out except that 106 g of the aqueous solution was used.

m-difluorobenzene yield 78.9% (45.0g
).

3 Into the apparatus of Example 1, 156.4 g of 35% hydrochloric acid (1,,
5 mol) of 2,4-difluoroaniline 64,
5 g (0.5 mol) was added to prepare 2,4-difluoroaniline hydrochloride.

After further diluting by adding 100 mQ of water, 50%-113
Add 79.2 g (0.6 mol) of P02 aqueous solution and
Cooled to 10°C.

After that, 36.2 g (0,525 mol) of sodium nitrite
was dissolved in 73 g of water and added dropwise while maintaining the temperature between 0 and 30°C. At the same time as the diazotization progressed and a diazonium salt was produced, the diazonium salt was dediazo-reduced by the hypophosphorous acid present, and m-difluorobenzene was produced while generating N2 gas. After the generation of N2 had stopped, the mixture was allowed to stand still for liquid separation, washed successively with brine, 5% aqueous NaHCO3, and brine, dried over MgSO4, and then distilled to obtain the desired product.

The boiling point was 281-83°C, and the yield was 45.6 g (80%).

Abandanshi - 50% -1 (50% instead of 79.2g of 3P02 aqueous solution
The same procedure as in Example 3 was carried out except that 106 g of %-Na)12Po2 aqueous solution was used.

The yield of m-difluorobenzene was 45.6 g (80%
)Met.

014 198 g of 50% hypophosphorous acid (1,5
mol) and 2,4-difluoroaniline 64.5
g (0.5 mol) was added to prepare hypophosphite of 2,4-difluoroaniline. Further, 100 mu of water was added to dilute the mixture, and the mixture was cooled to 0 to 10°C. Then, 3 sodium nitrite
Dissolve 6.2g (0,525mol) in 73g of water,
The temperature was kept at ~30°C and added dropwise.

At the same time as diazotization progresses and diazonium salt is produced,
The diazonium salt was dediazo reduced by the hypophosphorous acid present. The yield of m-difluorobenzene was 80% (
45.6g).

Tsugami Oku 6 208.6 g (2 mol) of 35% hydrochloric acid was added to the apparatus of Example 1.
) and 95 g of 2-fluoro-4-bromoaniline (
0.5m01) was added to obtain 2-fluoro-4-bromoaniline hydrochloride. Further, 100 mQ of water was added to dilute the mixture, and the mixture was cooled to 0 to 10°C. Then, 3 sodium nitrite
Dissolve 6.2g (0,525mol) in 73g of water,
The diazotization was completed by dropping while maintaining the temperature at ~10°C. Furthermore, 79.2 g of 50LH3P02 aqueous solution (0,5
mol) was added dropwise while maintaining the temperature at 0-30°C to perform de-diazo reduction. After the generation of N2 stopped, the liquid was separated by standing and washed sequentially with 1 saline solution, 5%-NaHCO3 aqueous solution, and saline solution.
After drying with MgSO4, the eye liquid m-bromofluorobenzene was obtained by distillation.

The boiling point was 147-149°C, and the yield was 78% (68.2 g).

50% instead of 79.2g of H3P02 aqueous solution
The procedure of Example 6 was repeated using 106 g of -NaH2po2 aqueous solution.

The yield of m-bromofluorobenzene was 76.6% (6
7g).

The target product m-chlorofluorobenzene was obtained according to the procedure of Example 6 using 2-fluoro-4-chloroaniline instead of 2-fluoro-4-bromoaniline.

Boiling point: 126-128°C. The yield was 77% (50.2 g).

Claims (1)

[Claims] 1, 2, 4- or 2, 6-halofluoroaniline is diazotized, and an aqueous solution of hypophosphorous acid or its salt is added dropwise to the resulting diazonium salt to dediazo-reduce the diazonium salt. A method for producing m-halofluorobenzene, comprising: A method for producing m-halofluorobenzene, which comprises diazotizing and removing diazo reducing 2,2,4- or 2,6-halofluoroaniline in the presence of hypophosphorous acid or a salt thereof. m-, which consists of adding an aqueous solution of hypophosphorous acid to 3, 2, 4- or 2, 6-halofluoroaniline to obtain a hypophosphite, and then diazotizing and dediazo-reducing the hypophosphite. Method for producing halofluorobenzene. m-difluorobenzene, which is obtained by diazotizing 4,2,4- or 2,6-difluoroaniline, dropping an aqueous solution of hypophosphorous acid or its salt onto the resulting diazonium salt, and dediazo-reducing the diazonium salt. manufacturing method. A method for producing m-difluorobenzene, which comprises diazotization-dediazo reduction of 5, 2, 4- or 2, 6-difluoroaniline in the presence of hypophosphorous acid or a salt thereof. m consisting of adding an aqueous solution of hypophosphorous acid to 6,2,4- or 2,6-difluoroaniline to obtain a hypophosphite, and then diazotizing and dediazo-reducing the hypophosphite.
- A method for producing difluorobenzene.