JPS59139345A - Preparation of diphenyl ether derivative - Google Patents

Abstract

PURPOSE:To prepare the titled substance useful as an intermediate of agricultural chemicals, etc. in high yield, by using the easily available 2-nitro-5-halogenoacetophenone and 3-chloro-4-hydroxybenzotrifluoride as the raw materials. CONSTITUTION:The titled compound can be prepared by reacting (A) 3-chloro-4- hydroxybenzotrifluoride with (B) 2-nitro-5-halogenoacetophenone (the halogen is F, Cl or Br) in the presence of an alkali, especially potassium carbonate, in an aprotic polar organic solvent in the presence or absence of catalyst. The charged equivalent ratios of A:B:alkali are preferably 1:(0.7-1.2):(0.8-1.1). The charge concentration of A is preferably 40-400pts.wt. based on 1,000pts.wt. of the solvent. The compound B can be synthesized by the conventional nitration of 3-halogenoacetophenone.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-chloro-4-trifluoromethyl-3'-
In producing acetyl-4'-nitrodiphenyl ether (hereinafter abbreviated as compound E), easily produced 2-nitro-5-7jL, oloacetophenone (hereinafter abbreviated as compound A) or 2'-: ) rho-5-chloroacetophenone (hereinafter abbreviated as compound B) or 2-
Regarding a method for obtaining compound E in high yield or high selectivity using nitro-5-bromoacetophenone (hereinafter abbreviated as compound C) and 3-chloro-4-hydroxypencitrifluoride (hereinafter abbreviated as compound ri). .

The compound E is a substance useful as an intermediate raw material for agricultural chemicals and the like. A conventional method for synthesizing compound E is to react metahydroxyacetophenone and 3,4-dichlorobenzotrioleide in an aprotic polar solvent in the presence of an alkali to produce 2-chloro-4-trifluoromethyl-3. ′−
There is a method of synthesizing acetyldiphenyl ether (hereinafter abbreviated as compound F) and nitrating it to obtain compound E (see, for example, US Pat. No. 4,263,227), but with this method, the yield of compound E is only about 60%. Also, in the nitration step, there are 3 nitrated regioisomers in addition to compound E.
Since 0 to 40% of by-products are produced, the upper limit of the yield is about 60%.
Therefore, there was a problem in that the total yield remained below 40%. In addition, there is a problem in that it is extremely difficult and costly to carry out an industrial separation operation between compound E and the nitrated positional isomer. Therefore, the route to obtain compound E by nitration after passing through compound F is not an industrially advantageous method due to the difficulty of separating by-products accompanying nitration, even if the synthesis yield of compound F can be improved. It can not be said.

Therefore, the present inventors made a concerted effort to avoid the difficulty of separating a large amount of nitrated positional isomers when passing through compound F, and to find a method for obtaining compound Et- with high yield or high selectivity. , discovered a method for producing E by reacting 2-nitro-5-haloke9noacetophenone (halodan is fluoride, chlorine or bromine) and a compound RI in an aprotic polar organic solvent in the presence of an alkali, The present invention has now been completed.

The raw material 2-nitro-5-1-lognoacetophenone used in the present invention can be easily obtained in high yield from 3-halodaneacetophenone by nitration using a conventional method.

According to the parent method, in addition to compound E, there are unreacted alkali salts of compounds, unreacted A, B, or C1, and unidentified by-products in the solution after the reaction, but if compound F is used, Since there are no nitrated positional isomers of compound E, the immediate release of compound E and recovery of compounds A, B or C and recovery of compound R are much easier than in conventional methods.

Therefore, according to the present invention, Compound E can be produced most inexpensively and easily compared to conventional methods.

In the present invention, potassium carbonate or potassium hydroxide is preferred as the alkali, and potassium carbonate is particularly preferred. It is also desirable that these alkalis be thoroughly ground in advance. It is preferable that these alkalis be added to the solvent at room temperature, reacted with the compound at room temperature with stirring for 30 minutes or more, then add compound A, B or C, and raise the temperature to a predetermined reaction temperature. The method of adding an alkali to a mixed solution of compound ASB or C and compound R at a predetermined reaction temperature is not preferred because it may reduce the selectivity of compound A, B or C. The required amount of alkali is adjusted to about the equivalent amount or slightly less than the amount of the compound, ie, preferably 0.8 to 1.1 equivalent ratio, more preferably 0.9 to 1.0 equivalent ratio. If the alkali is used in excess of the compound, not only the selectivity of the compound but also the selectivity of the compounds A, B or C is undesirably reduced. It is sufficient to charge Compound A, B, or C in the amount of Φ÷mol relative to the compound, and if it is in excess, the selectivity will decrease. Therefore, the charging equivalent ratio of compound to compound A (or B or C) to alkali is 1:0.7 to 1.
2:0.8-1.1 is suitable.

In addition, instead of adding alkali, add the compound in advance to alkali IJ.
m, and reacting this with compound A, B, or C in an aprotic polar organic solvent in the presence or absence of a catalyst causes no problem, but the operation becomes complicated.

The concentration of the compound is 40 to 1000 parts by weight of the solvent.
The amount is preferably 400 parts by weight, and even if it exceeds 400 parts, no improvement in conversion or yield can be expected and the selectivity will decrease slightly. Further, if it is less than 40 parts, the yield is low and no improvement in selectivity is observed, which is uneconomical.

When used in compounds, the solvent is dimethyl sulfoxide (
(hereinafter abbreviated as DMSO), dimethylacetamide, dimethylforamide, hexamethylphosphoric triamide (hereinafter referred to as H
It is preferable to use MPA (abbreviated as MPA), and the reaction temperature is 3.
Preferably the temperature is from 0°C to 90°C.

If it is less than 30°C, the reaction time will be too long, and since the reaction rate is sufficiently high, it is not necessary to exceed 90°C. Conversely, if the temperature is 110°C or higher, the yield tends to decrease.

On the other hand, when using compound B or C, the reaction conditions described below are preferable since the reactivity is lower than that of compound A. That is, the solvent is most preferably HMPA, DMSO or a mixed solvent thereof, and dimethylacetamide, dimethylformamide, N
- Solvents other than those mentioned above, such as methyl birolide y, result in poor yields. It is desirable that the water concentration in the solvent is as low as possible. Setting the reaction temperature range is important for controlling the conversion rate of compound B or C, and is 60 to 140°C, preferably 80 to 130°C.
Should be kept at ℃. If the temperature is lower than 60°C, the selectivity of compound B or C will decrease even if the reaction is carried out for a long time in an attempt to obtain a high yield. On the other hand, if the temperature exceeds 140°C, the selectivity for compound B or C will be low even if the reaction time is shortened.

The reaction time may be long as long as it does not reduce the selectivity of Compound B or C, but from an economical point of view it is typically 0.5 to 6 hours. The relationship between reaction temperature and reaction time is particularly preferably 80 to 110°C and 1 to 3 hours.

Adding calcium carbonate as a catalyst can reduce compound B
Alternatively, it is effective because it improves the selectivity of C and compound E and improves the yield of compound E. In this case, calcium carbonate is preferably added in an amount of 5 to 50 parts by weight per 100 parts by weight of the compound. Note that even if an alkali such as potassium carbonate is not added, and instead only calcium carbonate is added in a proportion to the compound, the reaction does not proceed.

In order to prevent deterioration of raw materials, products, and solvents, it is desirable to replace the space in the reactor with an inert gas such as 9-element gas and to shield it from light.

By selecting sufficiently strictly controlled conditions as described above, the conversion rate of compound B or C was 65 to 7 in HMPA solvent.
0%, selectivity of B or C to yield of compound E 60~
70%, and in DMSO solvent the conversion of compound B or C is 4
Compound E can be produced with a selectivity of B or C of 0 to 50% and a selectivity of B or C relative to the yield of Compound E of 60 to 70%. If you choose conditions that deviate even slightly from this, for example, if compound B is combined as a raw material, HM
When a reaction temperature of 150 °C in P A solvent is adopted, the yield of compound E is only 25% even if the reaction time is shortened to 30 minutes, while the conversion of compound B is 97% and the conversion of compound R is 92%. %, the selectivity of compound B with respect to the yield of compound E decreases to 26%, and the selectivity of compound B with respect to the yield of compound E decreases to 27%, making it an industrially disadvantageous production method. becomes.

The present invention will be explained in more detail with reference to Examples, Reference Examples, and Comparative Examples.Reference Example 1 Into a flask of 11, m-chloroacetophenone 51, O,
Add P (0.33 mol) and dropwise add 200 g of concentrated sulfuric acid while stirring vigorously at -10 to -15°C to become an orange transparent viscous liquid), followed by a mixed acid (70% nitric acid 46.6 mm) +
? Essential sulfuric acid (313y-) was added dropwise over about 20 minutes while maintaining the temperature at -5 to -10°C. After the dropwise addition was completed, stirring was continued for an additional 5 minutes, and the mixture was poured onto crushed ice. The resulting solid was washed with water in a separate furnace, extracted with dichloromethane, washed with water, separated with sochloromethane N'lc, dried and smoked, and dichloromethane was distilled off using an evaporator to obtain crude 2-nitro-5-chloroacetophenone 6.
5.5 pieces (pale yellow solid purity 90%) were obtained.

This was recrystallized and purified using ethanol-n-hexane to obtain pale yellow needle crystals (purity 98% or higher, melting point 60°C).

Quantitative analysis was carried out using high performance liquid chromatography (the column was a Waters Micron Dano 9-8, the developing solution was methanol-water (75+25)).

Example 1 IIMPA 103 in a 200 m/glass flask,
9.8 P (50 mmol) of Compound D and 3.45 f (25 mmol) of powdered potassium carbonate were added, and the mixture was stirred overnight at room temperature under a nitrogen blanket. Compound B
After adding 10.0 mmol (50 mmol), the temperature was raised to 100°C over about 15 minutes while stirring, and stirring was continued for 2 hours while maintaining the temperature at 100°C.

After that, after cooling to room temperature in a water bath, use approximately 500 m of acetonitrile and approximately 3001 nl of water! The contents of the flask were poured into a 11 beaker containing . 2N hydrochloric acid was added dropwise to this while stirring to make the solution acidic (pH measured with PH test paper;
2 to 3), and further added acetonitrile to bring the total volume to 1, followed by high performance liquid chromatography (hereinafter abbreviated as HLC).The column was Waters' Micro Nanda Pack C.
! 8) Quantified compound B3.3I? , compound D
5.3? s Compound E7.9y- was obtained. This means a yield of 44% and a conversion rate of compound B of 67% (selectivity of 66%).
%), the conversion rate of the compound was 46% (selectivity 96%).

Add 500 WL of toluene to this 11 solution and distill off the acetonitrile using an evaporator. After distilling off the acetonitrile, the residue from the pot consisted of two layers of toluene and water, of which the toluene layer was separated and thoroughly mixed with an alkaline aqueous solution prepared by adding 60 ml of 1N sodium hydroxide to 500 rni of water. After standing still, separate the toluene layer, distill off the solvent, and distill under reduced pressure to obtain compound B3.0/- and compound E7.3 as residue.
I got no. The recovery rate for each HLC analysis value was 9.
1%, equivalent to 92%. The aqueous layer of the residue after acetonitrile distillation and the aqueous layer of the toluene raffinate were combined, toluene was added thereto, and 2N hydrochloric acid was added dropwise to adjust the -1 of the aqueous phase to 2 to 3. The toluene phase was separated, the solvent was distilled off, and compound D4.7y- was obtained by distillation under reduced pressure. This corresponds to a recovery rate of 89% based on the value analyzed by ILC.

The following is a margin example 2 HMPA 51,! ;', Powdered potassium carbonate3.
45°C Compound B10. Og and Compound D9.8p were charged into a flask in the same manner as in Example 1, and the mixture was heated to 130% over about 25 minutes.
The temperature was raised to 130°C, and stirring was continued for 1 hour while maintaining the temperature at 130°C. Thereafter, it was post-treated in the same manner as in Example 1, and quantified by HLC to obtain 8.8 g of Compound E, 2.4 g of Compound B, and 3.2 g of Compound D. This yield is 49%, conversion rate of compound B is 76% (selectivity is 640, conversion rate of compound B is 640%, and conversion rate of compound B is 640%.
This corresponds to 7% (selection rate 73ch).

Comparative Example 1 The same operation as in Example 1 was performed except that the reaction temperature and reaction time were changed, and as a result of quantitative determination by HLC, the values shown in the table below were obtained.

Comparative Example 2 The same operation as in Example 1 was carried out except that the amount of potassium carbonate was changed, and as a result of quantitative determination by HLCK, the values shown in the table below were obtained.

Example 3 Compound D 5.90130 mmol in HMPA30.9)
and 2.079 (15 mmol) of powdered potassium carbonate were added, and the mixture was heated under a fluorine seal at room temperature for 1 hour.
, 32 g (30 mmol) and 75 min.
℃ sister got wet. After continuing stirring at 75°C for 6 hours, it was cooled to room temperature and 1! The contents were transferred to a volumetric flask. water layer 20
After adding 0M, add 6N hydrochloric acid IQal and bring the total volume to 11 with acetonitrile. This solution was quantified by HLC, and the yield of compound E was 36%, and the conversion rate of compound C was 46%.
(Selectivity: 78%) and conversion rate of compound RI: 32% (Selectivity: 89%).

Example 4 The same operation as in Example 3 was carried out except that the temperature was raised to 100 tl over about 20 minutes and stirring was continued for 2 hours at 1 oot. Selection rate 68
%), and the conversion rate of the compound was 60% (selectivity 86%).

Example 5 LOOwlW9y, DMSO55 in ring flask,! i'
3.45.9 (25 mmol) of powdered potassium carbonate, 0.50 g (5 mmol) of powdered calcium carbonate, and 9.89 (50 mmol) of compound 1) were added to the chamber under a nitrogen seal. The mixture was stirred for 1 hour. This was compounded by compound B10.0. ! After adding 17 (50 mmol), the temperature was raised to 100°C over about 15 minutes while stirring, and the temperature was increased to 100°C.
Stirring was continued for 2 hours while maintaining the temperature. After that, cool it to room temperature in a water bath, and add about 500 d of acetonitrile and 30 d of water in advance.
The contents of the flask were poured into a beaker containing 0.01 and 0.01.

While stirring, 2N hydrochloric acid was added dropwise to make the solution acidic (pH = 2 to 3 using pH test paper), and acetonitrile was further added to bring the total amount to 11. As a result of quantitative determination by HLC, the yield of compound E was 29%, the conversion rate of compound B was 45% (selectivity 64%),
A conversion rate of 56% (selectivity 52%) of the compound was obtained.

Comparative Example 3 Compound B or C was used, the reaction temperature and reaction time were changed, and the same operation as in Example 5 was carried out except for the hole. As a result of quantitative determination by HLC, the values shown in the table below were obtained.

Comparative Example 4 The same operation as in Example 5 was performed except that the amounts of potassium carbonate and calcium carbonate were changed, and the values shown in the table below were obtained as a result of quantitative determination by HLC.

Comparative Example 5 The same operation as in Example 3 was performed except that dimethylformamide was used as a solvent instead of HMPA, and the yield of compound E was 23%, and the conversion rate of compound C was 81% (selectivity 28%). %)
A conversion rate of 36% (selectivity 64%) of the compound was obtained.

Example 6 Put 055 g of DMS into a 200d glass flask,
9.80 g (50 mmol) of Compound D and 3.45 g (25 mmol) of powdered potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen blanket. To this compound A9.15
After adding about 10 g (50 mm 11 mol) of
The temperature was raised to 70°C over several minutes, and stirring was continued for 3 hours while maintaining the temperature at 70°C.

After cooling to room temperature through the drainage path, the contents of the flask were poured into a beaker No. 11 containing about 500 Kt of acetonitrile and 300 Kt of aqueous layer in advance. To this, 2N hydrochloric acid was added dropwise while stirring to make the solution acidic (pH 2 to 3 using pH test paper).
), and then add acetonitrile to make the overall view 11,
As a result of quantitative determination by HLC, Compound A: 0.18 g, Compound DO: 39 g, Compound E: 16.5 g. ! I got the result i'. This is a yield of 92%, a conversion rate of compound A of 98%,
This corresponds to a conversion rate of D of 96%.

patent applicant Asahi Kasei Industries, Ltd. patent application agent Patent attorney Akira Aoki Patent attorney Kazuyuki Nishidate Patent Attorney Ishi 1) Takashi Patent attorney Akira Yamaguchi

Claims (1)

[Claims] 1.3-Chloro-4-hydroxypencitrifluoride and 2-nitro-5-710gutacetophenone (halogen atom represents fluorine, chlorine or bromine atom) are mixed in the presence of an alkali in the presence or absence of a catalyst. 2-chloro-4-trifluoromethyl-3'-acetyl-4', characterized in that the reaction is carried out in an aprotic polar organic solvent in the presence of
-Production method of nitrodiphenyl ether.