JPS5927850A - Preparation of fluorobenzoic acid - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate of agricultural chemicals and pharmaceuticals, economically in an industrial scale, in high yield, by oxidizing a fluorotoluene derivative with an O2-containing gas in liquid phase using a catalyst comprising a combination of a heavy metal compond with a bromine compound. CONSTITUTION:The objective compound of formula II can be prepared by the liquid-phase oxidation of a fluorotoluene derivative of formula I (X is F, Cl or Br; Y is H or X) such as 2-chloro-4-fluorotoluene with an O2-containing gas in a solvent such as acetic acid, at 50-200 deg.C under atmospheric, positive or negative pressure in the presence of a catalyst comprising a heaby metal compound and a bromine compound such as NaBr, bromoacetic acid, etc. The heavy metal compound is preferably composed mainly of Co, Mn, Ce, Cr, Zr, Ni, etc., such as cobalt acetate, manganese acetate, Zr-acetyl-acetonate, etc., especially a Co compound. A heavy metal compound such as V, Fe, Cu, Ru, Rh, etc., may be used as a subsidiary component.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing substituted fluorobenzoic acids.

More specifically, the formula (wherein X represents F, CI or Br, Y represents IJ, i
”.

Using a heavy metal compound and a bromine compound as a catalyst, a fluorotoluene derivative represented by CI or Br is oxidized in a liquid phase in a molecular oxygen-containing gas to obtain the desired formula (where X and Y are the above-mentioned formula). This invention relates to a method for producing fluorozoic acids.

The compounds produced according to the present invention are all important compounds as intermediates for agricultural chemicals and medicines.

Examples of these compounds synthesized from the corresponding toluene derivatives by the liquid phase oxidation method include 2.
An example is the oxidation of -chloro-4-fluorotoluene. (C
A, 3'5 7966) However, the yield is low at about 38%.

As an example of oxidation with reed oxygen gas, the following yield: 8
2 exposure [: J, Org, Chem, 28 1759 (1963
)] yield is as low as 82%. Further, in this example, trivalent cobalt acetate is used, but this is difficult to prepare and is expensive, which is industrially disadvantageous. Furthermore, the oxidation reaction of the present invention and trivalent cobalt are completely different in terms of mechanism.

As a result of intensive research into a method for industrially producing the desired fluorobenzoic acids at low cost, the present inventors have discovered that the present invention is an extremely advantageous method industrially.

The present invention will be explained in detail below.

The catalyst used in the present invention is a combination of a heavy metal compound and a bromine compound.

Heavy metal compounds include Co, Mn, Ce, Cr
, Zr, Ni, or the like as a main component. Subcomponents include V, Fe, Cu, Ru, Rh,
Many heavy metal compounds can be used, such as Pd, 1-1f or Tll.

The heavy metal compound is preferably used in the form of a salt or complex that is soluble in the reaction system. That is, it is preferable to use the heavy metal in the form of an organic acid salt, an acetylacetone complex, an organic amine complex, or the like.

For example, cobalt acetate, manganese acetate, cobalt flopionate, manganese flopionate, cobalt benzoate, Zr
(CHa (CHz)3CI((C21-15)
COO〕4.

Zr (CH2C0CH+ COCH3)4 , zirconium naphthenate Zr O (OAS2 , Ni (OA
2. Examples include NiBr2 or nickel naphthenate.

A preferred method in the present invention is to use C as a heavy metal compound.
This is a method in which one or more heavy metal compounds are selected from each of the first group consisting of O, Mn, Ce, and Cr and the second group consisting of Zr and Ni, and a mixture of these is used. Among these, it is particularly preferable to use a heavy metal compound of Co from the first group as a main component.

When heavy metal compounds are used in combination as described above, a high reaction rate can be ensured and corrosion of a reactor, for example, a reactor made of titanium, can be significantly reduced.

The amount used is 2 x 10-3 as the concentration in the reaction system.
~3×10-' mole/4, particularly preferably 5×
It is suitable to use 10-3 to 2 x 10-' mole/J.

In addition, when one or more of each of the first group and the second group are selected and used as a mixture as described above, the heavy metal compound of the second group is 5 to 50% of the heavy metal compound of the first group.
0 mol%, especially 10-200 mol% is preferred.

Next, as the bromine compound used in the present invention, l3r2°H
Br, NaBr, KBr, NH4Br, CaB
r2. MgBr2. Inorganic bromine compounds such as CoBr2 or MnBr2, Br C1-12COOI-L Br2
CHCOOf1. Br5CCIjO, BrCll2C
I((Br)COOIL BrCll2COCH:+,
Br3 CC0OH, CHBr3. CIJBr2CJ
An organic bromine compound having an active bromine atom such as an aliphatic bromine compound such as -JBr2 is used. Organic bromine compounds having a carbonyl group are particularly good.

The amount used is 5 x 10-3 to 3 as the concentration in the reaction system.
X 10-' mo1e/4 Particularly preferably 1×1
It is desirable to use 0-2 to 2X 10-'mole/4.

In addition, as co-catalysts, CH3COONa, Cl-l
3COOK or a heterocyclic nitrogen-containing base such as pyridine, picoline, lutidine, triethylamine, triethanolamine, jetanolamine, methylamine, dimethylamine, primary, secondary, or tertiary amine; or interphase As a transfer catalyst, a quaternary ammonium salt such as cetyltrimethylammonium bromide, benzyltrimethylammonium hydroxide, tri-octyl-methylammonium chloride, or tetrabutylammonium chloride is used as a transfer catalyst.
It may be added at a concentration of about O-' mole//e3. Oxidatively stable compounds are used as reaction solvents, and good results are obtained when lower fatty acids are used as at least one component of the solvent. Among lower fatty acids,
Particularly suitable are acetic acid, propionic acid, etc.

The amount of solvent used is, for example, 0.03 to 1
It is preferable to use it in an amount of about 0 times by weight, but it is particularly industrially advantageous to use it in an amount of about 0.05 to 5 times by weight. Water is produced as the oxidation reaction progresses. When water is present in a large amount, the reaction rate decreases. Therefore, it is desirable to remove it by appropriate means (for example, distillation, etc.). Acid anhydride or the like may be added to the reaction system.

The reaction usually starts easily, but if it contains impurities, it is sometimes necessary to add a small amount of initiator. Peroxides, especially organic peroxides, are suitable as these initiators. Also, azobisisobutyronitrile (AIBN)
Compounds that generate radicals by thermal decomposition, such as, can also be used.

As the oxygen-containing gas, oxygen gas and air are economical, but they can be used by appropriately mixing them with an inert gas such as nitrogen or helium 002.

The reaction temperature is suitably carried out at about 50 to 200C, particularly preferably about 50 to 180U.

The reaction can be carried out under normal pressure, increased pressure, or slightly reduced pressure. Normal pressure is convenient in terms of equipment, but elevated pressure has the advantage of increasing the reaction rate.

All of these must be carried out under strong stirring.

Specific examples of typical compounds of the formula (Il) that are raw materials of the present invention include 2,4-cyfluorotoluene, 2-10-4-fluorotoluene, 2-bromo-4-fluorotoluene, 3- 10rho 4-fluorotoluene, 3-bromo-4-fluorotoluene, 2-.170o-4,6-cyfluorotoluene, 2
．． 6-cyclo-4-fluorotoluene, 2-70 mo4
．． 6-cyclotoluene, 2,6-dibromo-4-fluorotoluene, 4-1'rolo-2-fluorotoluene, 4-
Bromo-2-fluorotoluene, 6-chloro-2,4-cyclotoluene, 4.6-dichloro-2-fluorotoluene, 6-fluoromo-2,4-difluorotoluene, 2.5
-difluoro-l-luene, 2-chloro-5-fluorotoluene, 2-bromo-5-fluorotoluene, 2.5=cycloefluoro-fluorotoluene, 2-bromo-5-chloro-4
-fluorotoluene, 2-bromo-6-chloro-4-fluorotoluene, and the like.

This will be explained in detail below using examples.

Example 1 Into a 200m6 glass 40 flask, 1.21 g of cobalt acetate tetrahydrate, 0.0125' of manganese acetate tetrahydrate, and 0.0 g of sodium bromide were added. IP, 2-chloro-4-fluorotoluene14.
After charging 20ml of 4g-1 acetic acid and raising the temperature to 90C,
Air was introduced while stirring vigorously.

The amount of air introduced is such that the oxygen concentration at the outlet of the reaction flask is 5 to 1.
It was adjusted to be 3%. Approximately 6 hours after the start of the reaction, 10.89 g of acetic anhydride was added dropwise, and then air was introduced. Oxygen absorption becomes slight after about 10 hours, but after raising the temperature to 100C and reacting for an additional 1.5 hours, the contents were poured into ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. , the extract was concentrated to give 15.7 g (yield 90.3%)
2-chloro-4-fluoro-benzoic acid was obtained. The melting point was 175-176C.

Calculated value 48.17% 2.30% 0% Example 200 ml with 2° condenser! Cobalt acetate tetrahydrate 0.3365', manganese acetate tetrahydrate 0.0033P, and sodium bromide 0.278f in a glass autoclave.
ig, 205' of 2-chloro-4-fluorotoluene, and 70 ml of acetic acid were charged, and the temperature was raised to 140°C. Thereafter, air was introduced while stirring vigorously to bring the pressure inside the autoclay to 9 aim. ] 20-200 mli/
Fresh air was supplied above the liquid level in the system so as to remove waste gas from the autoclave at a rate of min and keep the pressure constant. The oxygen concentration in the waste gas was adjusted to 2.5% to 65%. After 3 hours of reaction, oxygen absorption became small, so the reaction was stopped and cooled. After cooling, the precipitated crystals were taken from house to house and dried to yield 78.6! V-2-chloro-4-fluorobenzoic acid was obtained. Concentrate the p liquid and get 3.0 more! The target product i' was obtained with a total yield of 89.4%.

Example 3 Cobalt acetate tetrahydrate was added to a glass 4-day flask measuring 51°C.
After charging 0J, 281.0J of bromoacetic acid, 3477777 of 2-chloro-4-fluorotoluene, and 10100O of acetic acid and raising the temperature to 85'C, oxygen was introduced while stirring vigorously. The amount of oxygen introduced was 2020-2O0/min.

The reaction temperature was gradually raised to 115C.

After the reaction was carried out for 6 hours, the contents were poured into ice water and the precipitated crystals were filtered and dried.374! 2-chloro-4-fluorobenzoic acid of i' (yield 893%) was obtained.

Example 4 24 cobalt acetate tetrahydrate in 21 glass 40 flasks
．． 95', bromoacetic acid 7.475'-,2-bromo-4
-7o) Luene 223.9 P, Q'H acid 350
ml was charged, the temperature was raised to 90C, and oxygen was introduced while stirring vigorously. (50~200 m1./min
). Since the reaction temperature rises, keep it at 90-100 m while cooling.
I kept it at 3C. The reaction was completed in about 5 hours, and the contents were poured into ice water, extracted with ethyl acetate, and the extract was concentrated.
After adding n-hexano and cooling, the precipitated crystals were filtered and dried to obtain 247.5 y- (yield 95.4%) of 2-bromo-
White crystals of 4-fluoro-benzoic acid were obtained. In addition, n-hexano was concentrated to obtain the target product 111 (yield 4.2%). The melting point was 1.72.8-174.2 tl:'.

The elemental analysis values were as follows.

CI (N Actual value 38.42% 1.80% 0% Calculated value
38.35% 1.82% 0% Example 5 Cobalt acetate 4 hydrate 5
05', manganese acetate tetrahydrate 0.05 goo, monobromoacetic acid 28.5! ? , [Th acid 11.2-chloro-4-
Charge fluorotoluene 3471, raise the temperature to 80'C, and introduce oxygen (20 to 200 ml) while stirring vigorously.
/ m1n). After reacting for 5 hours while maintaining the reaction temperature at 80C to 110C, the contents were placed in ice water and the precipitated white crystals were filtered and dried to give 380P (yield 9).
0.7%) of 2-chloro-4-fluorobenzoic acid was obtained.

Example 6 Cobalt acetate 4 was placed in a 300m1 glass flask.
Water 4.64g-1 manganese acetate/4 water 0.02! i
2.6 g of bromoacetic acid - 93 ml of acetic acid was charged. Here, 2,6-dipromo-4-fluoro-toluene is added to 6
0g・Preparation temperature was raised. Air was blown into the mixture at 80C with vigorous stirring.

The reaction was carried out for 5 hours while adjusting the air flow rate so that the oxygen concentration in the waste gas was 5 to 12%. 10 by the end of the reaction
The temperature was gradually raised to 0C. After the reaction was completed, acetic acid was distilled off, water was added, and the precipitated crystals were collected from door to door. After drying, 631 white 2,6-dipromo-4-fluorobenzoic acid was obtained.

Yield 95%.

The melting point was 142C to 144C, and the elemental analysis values were as follows.

CI-IN Actual value 28.10% 0.99% 0% Calculated value
2822% 1.02% 0% Example 7 Cobalt acetate was added to a 100rnl glass 40 flask.
4 hydrate 0.90 P-1 manganese acetate 4 hydrate 0, OO
'90P, bromoacetic acid 0.50 F-13-bromo-4
- 20% fluorotoluene and 407% acetic acid were charged. 85
The temperature was raised with C'j, and air was blown in while stirring vigorously. The flow rate was adjusted so that the oxygen concentration in the waste gas was 5 to 12%, and the reaction was carried out for 6 hours. After the reaction was completed, the precipitated crystals were poured into ice water and dried. White 3-bromo-4-fluorobenzoic acid 209 was obtained. Yield 86.1%.

The melting point was 134C to 136C, and the elemental analysis values were as follows.

CHN Actual value 3825% 1884% 0% Calculated value 3
839% 1.84% 0% Example 8 Co (OAC) was added to a 50 m/4 glass 4-day flask.
2-4N20.0.336 Ft, Mn (OAC)
2-4II200.0033P.

Na13r 0.278 P, Na0A, CO, 332
Ft, Zr[CJ(2(O(2)aCIHC2115
) COO] 0.448 i%, 2-chloro-4-fluoro
Prepare toluene 10 Fix acetic acid 20m6, 85C
The temperature rose to . While stirring vigorously, add 35 ml of air/
A reaction was carried out on the liquid surface at min. After 7.5 hours, no oxygen was absorbed and only a trace amount of the raw material could be detected by gas chromatography. Some 2-chloro-4-fluorobenzyl bromide remains t, = (7') te3
Most of the residue was converted into hrreflux L, 2-chloro-4-fluorobenzyl acetate, and then concentrated to dryness using a rotary evaporator. Aqueous sodium hydroxide solution was added to dissolve the crystals, and then activated carbon was added. After the activated carbon was separated, pig acid was added for acid precipitation, and the precipitated white crystals were allowed to pass and dried.

11.05P of pure 2-chloro-4-fluorobenzoic acid was obtained.

The yield was 915%.

Example 9 In a 300 m1 titanium autoclave equipped with a condenser, Co(OAC)z-4H200,336P, M
n(OAC)2-4I-1200,0033Lj-1N
aBr 0.278 PSZr -acetylacetonate 0.4397,2-dicorro-4-fluorotoluene 2D
70 ml of acetic acid was charged and the temperature was raised. Air was introduced under strong stirring at 140C. The internal pressure was 9 a, Lm.

Waste gas was extracted from the autoclave at a rate of 200-300 ml/mJn, and fresh air was supplied above the liquid level in the system to keep the pressure constant. A slight induction period was observed at first (approximately 10 minutes), but after that oxidation proceeded smoothly and the oxygen concentration in the waste gas was maintained at 3 to 5%. After 2 hours, oxygen absorption stopped and the temperature was cooled. After cooling to room temperature, the autoclave was opened and the precipitated crystals were separated from each other.The crystals were washed with water and dried to obtain 19.9 g of 2-chloro-4-70-benzoic acid. The target product of .25P was recovered and the total yield was 21.15P, which corresponds to a yield of 878%.During this reaction, 1.035zX 2.89cr
A material test plate made of nX0.2 cm titanium was installed, but no change in weight was observed and the surface condition did not change at all.

The same procedures as Reference Example 1 and Example 9 were carried out, except that 7r-acetylacetonate was not added at full heat. After 4 hours of reaction, oxygen absorption stopped, so the same treatment as in Example 9 was carried out. 2-chloro-
The total yield of 4-fluorobenzoic acid was 89.4%.

The same material test plate as in Example 9 was severely corroded, with a corrosion rate of 3.73 mm/Y. Of course, the autoclave also suffered considerable corrosion.

Example 10 Co (OAC) was added to a 105O glass four-day flask.
2-4020 to 0.1495', Ce (OAC)3-
1-120 to 0.00605'Na 13r to 0.12
1Of of 4P, 2-chloro-4-fluorotoluene and 20ml of acetic acid were charged. The temperature was raised to 90C, and air was flowed at a rate of 35 me/min while stirring vigorously. After the reaction started, the oxygen concentration in the rotten gas was 18-19%.

At this point, the reaction was allowed to proceed for a while, but no change was observed, so 0.293 P of 7r-acetylacetonate was added.

Then, the oxidation rate suddenly increased and the oxygen concentration in the waste gas reached 8.0% within 10 minutes. As a result, the reaction rate was improved by more than four times at this point. After a total reaction time of 12 hours, acetic acid was distilled off, water was added to the residue, filtered through p, and dried.
．． 5P (Y: 86.9%) 2-chloro-4-fluorobenzoic acid was obtained.

Example 11　Actual M Liquid phase oxidation was carried out in exactly the same manner as in Example 10, except that 2-chloro-4-fluorotoluene was changed to 2-bromo-4-fluorotoluene (10 L!-).

Since no oxygen absorption was observed after a reaction time of 10.5 hours, the same procedure as in Example 10 was carried out to obtain 10.85'-2-bromo-4-fluorobenzoic acid.

Yield 93.2%.

Example 12 Co (OAC)2- was placed in a 22° glass 4-day flask.
4 I42018.2 g-1Ni (OAC)2-4
l-I209.1 f, Br CI-+2COOII
7.5? , 296 ml of acetic acid, 134 P of acetic anhydride.

2-Bromo-4-fluorotoluene 240.19- was charged, and after raising the temperature to 85 tT, air was introduced while stirring vigorously (
50-300ml/min L. 85~100C
The reaction was completed in 13 hours, and the contents were poured into ice water and the precipitated F crystals were filtered and dried, resulting in white crystals 274, . 3
2-bromo-4-fluorobenzoic acid of P (yield 98.6%) was obtained.

Example 13 Co (OAC
)2-4H200,9341, Mn(OAC)2-4
H2O0,0092g-1NaBrO,773f/
-, Zr-acetylacetonate) 1.46y, acetic acid 1
00mA 12-chloro-4-fluorotoluene 50P was charged and the temperature was raised. After reaching 85C, air was flowed at 120 ml/min while stirring vigorously, and a small amount of methyl ethyl ketone peroxide was added.

The reaction was carried out at 85-93C for 13 hours. The oxygen concentration in the waste gas was between 7 and 11%.

After the reaction was completed, 2.5% sodium acetate was added and heated at about 120C.
I did a 5 hr reflux. While hot, the reaction mixture was poured into 300 ml of water, and after cooling, precipitated crystals were collected from door to door.

After drying in a desiccator, 5427 2-chloro-4-fluorobenzoic acid was obtained, and 0.8y-2-chloro-4-fluorobenzoic acid was further recovered from the p solution.

The total yield was 91.0%.

Example 14゜7,2-bromo-4-fluorotoluene 453.6y-1
Even after charging AcOHI A and raising the temperature to 80C, oxygen gas was introduced while stirring vigorously (20 to 200 m1/
m1n) L, ta. After reacting for 8 hours while maintaining the reaction temperature at 80-100C, the contents were poured into ice water and the precipitated white crystals were filtered and dried to give 473 fF (yield 90.
0%) of 2-bromo-4-fluorobenzoic acid was obtained.

Example 15 3! Co (OAC)2-4 in a glass 4-day flask
112031, 2551, Ni (OAc)z-41-
Jzo 15.6 P, Mn(OAS, -4,1-1
200, I P, Cl-13 COONa 5.2 Is
', bromoacetic acid 2921, ACOI-J 1-e, 2-
After charging 472.55' of bromo-4-fluorotoluene and raising the temperature to 80C, oxygen gas was introduced (20 to 200 ml/ml) while stirring vigorously.

After reacting for 6 hours while maintaining the reaction temperature at 70C to 100C, the contents were poured into ice water and the precipitated white crystals were filtered out and dried to yield 473! - (yield: 90.0%) of 2-bromo-4-fluorobenzoic acid was obtained.

Example 16゜ Mn (OAC) of Example 15 2-41 (zo 0.
Cr (OAC)3-1-1zO0 instead of I Fj'
2-bromo-4-fluorobenzoic acid was obtained in a yield of 92% by carrying out the reaction in the same manner as in Example 15, except that 1 g of 2-bromo-4-fluorobenzoic acid was used. Patent applicant: Nippon Kayaku Co., Ltd.

Claims (2)

[Claims] (1) Formula (wherein X represents I", CI or Br, Y represents H, 1"
. A formula (where X and Y means the above-mentioned benzoic acids] (2) First group of manufacturing methods according to claim (1), in which one or more heavy metal compounds are selected from each of the following two groups as heavy metal compounds and mixed together: Co, Mn, Ce , Cr 2nd group: Zr, sushi