JP2628842B2 - New fluorobenzotrichloride compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fluorobenzotrichloride compound which is useful as an intermediate such as a medicine.

[0002]

2. Description of the Related Art Hitherto, a trichloromethyl group has been considered as a precursor of a carboxyl group. However, p-difluorobenzene [J. Yurmi et al., Yiyao Gongye, 16 (8), 370 (19)
85); CA, 104, 50593 g] and the reaction of o-difluorobenzene [JP-A-63-188643] with carbon tetrachloride gives bisphenyldichloromethanes in high yield and almost no benzotrichloride. Not been.

On the other hand, 2,4-dichloro-5-fluorobenzotrichloride is obtained by chlorinating 2,4-dichloro-5-fluorotoluene under ultraviolet irradiation [
No. 58-74638]. 2,4-Dichloro-5-fluorobenzoic acid can be prepared by a method of hydrolyzing 2,4-dichloro-5-fluorobenzotrichloride [Japanese Patent Laid-Open No. 58-74638], 1,3-dichloro-4-fluoro A method of acetylating benzene and subjecting it to a haloform reaction [EP 1760261
(1986); DE 3435392 (1986); JP-A-61-85350],
It is known that 1-bromo-2,4-dichloro-5-fluorobenzene is reacted with magnesium to obtain a Grignard reagent, which is then reacted with carbon dioxide [JP-A-60-237069]. I have.

Further, 2-chloro-4,5-difluorobenzoic acid is used to hydrolyze 2-chloro-4,5-difluorobenzotrifluoride [Japanese Patent Laid-Open No. 62-108839] and 1-chloro- It is known that 3,4-difluorobenzene is obtained by acetylation and the resulting product is subjected to a haloform reaction [Japanese Patent Laid-Open No. 64-45322].

[0005] 2-Bromo-4,5-difluorobenzoic acid is obtained by hydrolyzing 2-bromo-4,5-difluorobenzonitrile [I. Cervena et al., Coll.
ect.Czech.Chem.Commun., 42,2001 (1977); CA.87,201469
e].

As for 2,4,5-trifluorobenzoic acid, 2-amino-4,5-difluorobenzoic acid is used.
[GCFinger et al., Illinois State Geol.Survey Cir
c., 199, 15 (1955)], or its ethyl ester form [J.
I.deGraw et al., J. Chem. Eng. Data, 13 (4), 587 (1968)]
alz-Schiemann reaction or a method of obtaining in low yield by Balz-Schiemann reaction and hydrolysis, 1-bromo-2,
A method of reacting a Grignard reagent of 4,5-trifluorobenzene with carbon dioxide [JP-A-58-150543;
JP-A-58-188839], 1-bromo-2,4,5-
A method of cyanating trifluorobenzene and hydrolyzing it [JP-A-60-72885; EP 191185 (1986)],
A method of hydrolyzing 2,4,5-trifluorobenzoic halide, a method of hydrolyzing 2,4,5-trifluorobenzotrifluoride [Japanese Patent Laid-Open No. 62-108839],
And a method of decarboxylating 3,4,6-trifluorophthalic acid [JP-A-64-52737] and the like are known.

Further, 2,3,4-trichloro-5-fluorobenzoic acid nitrates 2,4-dichloro-5-fluorobenzoic acid to give 2,4-dichloro-5-fluoro-3.
A method of obtaining nitrobenzoic acid, followed by reduction and a Sandmeyer reaction [JP-A-63-88157] is known.

As described above, the conventional methods have problems such as irradiation with ultraviolet rays, haloform reaction, Grignard reaction and Sandmeyer reaction with low batch efficiency, and use of diazonium salts and hydrocyanic compounds which are harmful to the human body. Also, the material of the reaction vessel was limited, and it was not industrially advantageous.

[0009]

SUMMARY OF THE INVENTION The object of the present invention is to overcome the aforementioned disadvantages of the prior art.

[0010]

SUMMARY OF THE INVENTION The present invention provides a 4-fluorobenzotrichloride compound useful as an intermediate for medicines and the like.

That is, the present invention provides 2-chloro-4,5-
Provides difluorobenzotrichloride.

[0012]

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The present invention also provides 2,4,5-trifluorobenzotrichloride.

[0014]

Embedded image The present invention also provides 2-bromo-4,5-difluorobenzotrichloride.

[0015]

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Further, the present invention provides 2,3,4-trichloro-5-fluorobenzotrichloride.

[0017]

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The present inventors reacted a fluorobenzene compound represented by the following general formula (I) with carbon tetrachloride in the presence of a Lewis acid catalyst to obtain a fluorobenzotrichloride compound represented by the following general formula (II) Was. Further, they have found that a hydrobenzoic acid represented by the following general formula (III) can be produced by hydrolyzing them.

[0019]

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(In the formula, X ₁ and X ₃ represent a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and X ₂ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.)

The present inventors have studied 1,3-dihalogeno-4-fluorobenzene or 1,2,3-trihalogeno-4.
As a result of intensive studies on the Friedel-Crafts reaction between fluorobenzene and carbon tetrachloride, bis (2,4-dihalogeno-5-fluorophenyl) dichloromethane or bis (2,3,4-trihalogeno-5-fluorophenyl)
The by-product of dichloromethane is suppressed, and the desired 2,4-
It has been found that dihalogeno-5-fluorobenzotrichloride or 2,3,4-trihalogeno-5-fluorobenzotrichloride can be obtained in good yield.

The method for obtaining the compound of the present invention can be represented by the following reaction formula.

[0023]

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(In the formula, X ₁ and X ₃ represent a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and X ₂ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.)

The trichloromethylation reaction is carried out in carbon tetrachloride
Preferably in excess carbon tetrachloride, under a Lewis acid catalyst, 1,3-dihalogen-4-fluorobenzene or
The reaction is carried out by adding 2,3-trihalogen-4-fluorobenzene, preferably dropwise.

That is, the reaction is carried out under conditions in which a fluorobenzotrichloride compound-Lewis acid complex is less likely to be produced than a carbon tetrachloride-Lewis acid complex, thereby suppressing the formation of bisphenyldichloromethanes. Fluorobenzotrichloride can be obtained in good yield.

The amount of carbon tetrachloride used is 1,3-
Dihalogeno-4-fluorobenzene or 1,2,3-
2-20 relative to trihalogen-4-fluorobenzene
It is 1 mol, preferably 4 to 10 mol, and used as a reactant and a solvent.

Examples of the Lewis acid catalyst include aluminum chloride, aluminum bromide, and aluminum chloride-sodium chloride (1: 1) complex. Aluminum chloride is industrially preferable, and the amount of 1,3-dihalogeno is used. The amount is 1 to 3 mol, preferably 1.5 to 2.0 mol, per 1 mol of -4-fluorobenzene or 1,2,3-trihalogen-4-fluorobenzene.

The reaction temperature is generally 10 to 80 ° C., preferably 60 to 80 ° C., and the reaction time is generally 10 to 60 minutes. After completion of the reaction, the desired 2,4-dihalogeno-5-fluorobenzotrichloride or 2,3,4-trihalogeno-5-fluorobenzotrichloride can be easily obtained by ordinary post-treatment and distillation.

The hydrolysis reaction is carried out in aqueous sulfuric acid.
The reaction conditions such as the sulfuric acid concentration, the weight ratio to the trichloromethyl form, the reaction temperature and the time of the hydrolysis reaction of the present invention may be appropriately selected as appropriate, but 85 to 95% sulfuric acid is converted to the trichloromethyl form. It can be carried out at a temperature of 30 to 100 ° C. and a reaction time of 1 to 5 hours, using approximately 1 to 4 parts by weight per 100 parts by weight.

Hydrolysis of 2,4-dihalogeno-5-fluorobenzoic acid or 2,3,4-trihalogeno-5-fluorobenzotrichloride obtained by hydrolysis of 2,4-dihalogeno-5-fluorobenzotrichloride 2,3,4-Trihalogeno-5-fluorobenzoic acid obtained by decomposition can be obtained in high purity and high yield by usual post-treatment and filtration.

Hereinafter, embodiments of the present invention will be described more specifically.

[0033]

【Example】

Example 1 97 ml (1 mol) of carbon tetrachloride and aluminum chloride were placed in a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel.
7 g (0.2 mol) were charged and 1-chloro-
14.9 g (0.1 mol) of 3,4-difluorobenzene
Was added dropwise over 1.5 hours so that hydrochloric acid gas was slowly generated. The generated hydrochloric acid gas was absorbed by an aqueous sodium hydroxide solution. After the completion of the dropwise addition, the mixture was reacted for 10 minutes, cooled to room temperature, and then poured into 300 ml of ice water.

The organic layer was separated, washed with 100 ml of water, then with 100 ml of a 5% aqueous sodium hydrogen carbonate solution and further with 100 ml of water. After carbon tetrachloride was distilled off, the remaining liquid was distilled under vacuum to obtain 17.4 g of 2-chloro-4,5-difluorobenzotrichloride (yield: 65.
4%). b. p. 104-106 ° C / 8mmH
g, n ²⁰ _D 1.540 and purity 98.2%.

The structure of this product was confirmed by the following analysis.・ IR analysis (neat) (cm ^-1 ): 3060,1601,1485,765 (CC
l ₃ ).

NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in (CD ₃ ) ₂ CO: δ -132.5pp
m (d, d, d, J _FF = 20.6Hz, J _FH = 9.9Hz, J _FH = 8.1Hz), δ -13
7.5 ppm (d, d, d, J _FF = 20.6 Hz, J _FH = 11.9 Hz, J _FH = 7.3 Hz).

< ¹ Hnmr> δppm from TMS in (CD ₃ ) ₂ CO:
δ 7.70ppm (1H, d, d, J _HF = 9.9Hz, J _HF = 7.3Hz), δ 8.21p
pm (1H, d, d, J _HF = 11.9Hz, J _HF = 8.1Hz).

Elemental analysis: 53.4% Cl, C
Calculated value for ₇ H ₂ Cl ₄ F ₂ : Cl 53.33
%.

Next, 9 ml was placed in a 100 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel.
47 g of 5% sulfuric acid was charged and the mixture was heated at 40 to 45 ° C.
Chloro-4,5-difluorobenzotrichloride 17.
4 g were added dropwise. The generated hydrochloric acid gas was absorbed by an aqueous sodium hydroxide solution. After reacting for 1 hour, ice water 300
The solution was poured into the resulting solution, and the precipitated crystals were separated by filtration. The filtered crystals were washed with a small amount of cold water and dried to obtain 12.1 g (96% yield) of 2-chloro-4,5-difluorobenzoic acid. m. p. 103-105 ° C.

[0040] [Example 2] Using the apparatus of Example 1, 1, 2-dichloroethane 50
ml, 9.7 ml of carbon tetrachloride (0.1 mol) and 26.7 g of aluminum chloride (0.2 mol)
14.9 g of 1-chloro-3,4-difluorobenzene
(0.1 mol) was added dropwise at 30 ° C. in 30 minutes.
The reaction was performed at 0 ° C. When processing is performed in the same manner as in Example 1, 2-
Chloro-4,5-difluorobenzotrichloride is 2.
48 g (yield 9.3%) and a distillation residue were obtained. When the distillation residue was recrystallized from toluene, 15.1 g (80% yield) of by-product bis (2-chloro-4,5-difluorophenyl) dichloromethane was obtained as white crystals. m.
p. 143-144 ° C.

The structure of this by-product was confirmed by the following analysis.

IR analysis (KBr) (cm ^-1 ): 3050, 1590, 146
0.

NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in (CD ₃ ) ₂ CO: δ -133.2pp
m (d, d, d, J _FF = 22.6Hz, J _FH = 10.0Hz, J _FH = 8.3Hz), δ -1
36.8ppm (d, d, d, J _FF = 22.7Hz, J _FH = 12.1Hz, J _FH = 7.5H
z).

< ¹ Hnmr> δppm from TMS in (CD ₃ ) ₂ CO:
δ 7.78 ppm (1H, d, d, J _HF = 10.0 Hz, J _HF = 7.5 Hz), δ 8.36p
pm (1H, d, d, J _HF = 12.1Hz, J _HF = 8.3Hz).

Elemental analysis: Cl 37.5%, C
Calculated value for ₁₃ H ₄ Cl ₄ F ₄ : Cl 37.52
%.

Example 3 In the same manner as in Example 1, a reaction was carried out by reacting 38.3 g of a crushed aluminum chloride-sodium chloride (1: 1) melt instead of 26.7 g of aluminum chloride. However, 14.1 g (yield 53%) of 2-chloro-4,5-difluorobenzotrichloride was obtained.

REFERENCE EXAMPLE 1 97 ml of carbon tetrachloride was placed in a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel.
(1 mol) and 26.7 g of aluminum chloride (0.2
Mol), and 16.5 g (0.1 mol) of 1,3-dichloro-4-fluorobenzene was added dropwise under reflux, followed by reaction for 20 minutes. When post-processing is performed in the same manner as in Example 1,
17.7 g (62.6% yield) of 2,4-dichloro-5-fluorobenzotrichloride was obtained. b. p. 94
９５95 ° C./1 mmHg, n ²⁰ _D 1.577, purity 98.
1%.

The structure was confirmed by the following analysis.・ IR analysis (neat) (cm ^-1 ): 3070,1570,1455,767 (CC
l ₃ ).

NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in (CD ₃ ) ₂ CO: δ -115.5pp
m (d, d, J _FH = 10.3Hz, J _FH = 6.8Hz). < ¹ Hnmr> δppm from TMS in (CD ₃ ) ₂ CO: δ7.58ppm (1
H, d, J = 6.8Hz), δ 7.99ppm (1H, d, J = 10.3Hz).

Elemental analysis: 62.7% Cl, C
Calculated for ₇ H ₂ Cl ₅ F: 62.78% Cl.

Next, as in Example 1, 40 g of 95% sulfuric acid
17.7 g of 2,4-dichloro-5-fluorobenzotrichloride was added dropwise thereto at 40 ° C., hydrolyzed, and treated similarly to obtain 12.7 g of 2,4-dichloro-5-fluorobenzoic acid ( 97%). m. p. 14
1-142 ° C.

Example 4 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were placed in a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel. Mol), and 13.2 g (0.1%) of 1,3,4-trifluorobenzene was added under reflux.
Mol), and reacted for 20 minutes. By treating in the same manner as in Example 1, 2,49,5-trifluorobenzotrichloride (7.49 g, yield 30%) was obtained. b.
p. 93-95 ° C./20 mmHg, n ²⁰ _D 1.506,
The purity was 98.3%.

The structure was confirmed by the following analysis.

IR analysis (neat) (cm ^-1 ): 3060, 1620, 15
05,767 (CCl ₃ ).

NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in (CD ₃ ) ₂ CO: δ -104.4 pp
m (d, d, d, J _FF = 20.6Hz, J _FH = 10.8Hz, J _FH = 6.7Hz), δ -1
29.5ppm (d, d, d, d, J _FF = 20.6Hz, J _FF = 10.8Hz, J _FH = 10.8H
z, J _FH = 6.7Hz), δ -141.7ppm (d, d, d, J _FF = 20.6Hz, J _FH
= 10.8Hz, J _FH = 7.9Hz).

< ¹ Hnmr> δppm from TMS in (CD ₃ ) ₂ CO:
δ 7.49 ppm (1H, d, d, d, J _HF = 10.5Hz, J _HF = 10.5Hz, J _HF =
6.7Hz), δ 7.99ppm (1H, d, d, d, J _HF = 10.8Hz, J _HF = 7.9Hz,
J _HF = 7.9 Hz).

Elemental analysis: Cl 42.4%, C
Calculated value for ₇ H ₂ Cl ₃ F ₃ : Cl 42.64
%.

Next, this was replaced with 95% as in Example 1.
7.49 g of 2,4,5-trifluorobenzotrichloride was added dropwise at 40 ° C. to 30 g of sulfuric acid, and hydrolysis was carried out.
By the same treatment, 2,4,5-trifluorobenzoic acid (5.0 g, yield 94.6%) was obtained. m. p. 95
~ 96 ° C.

Example 5 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were placed in a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel. Mol) and 1 under reflux
19.3 g of -bromo-3,4-difluorobenzene
(0.1 mol), and the mixture was reacted for 30 minutes. When treated in the same manner as in Example 1, 21.1 g of 2-bromo-4,5-difluorobenzotrichloride was obtained (yield: 68.1).
%) Obtained. b. p. 96-98 ° C / 1mmHg, n
²⁰ _D 1.563, was 98.6% pure.

The structure was confirmed by the following analysis.・ IR analysis (neat) (cm ^-1 ): 3050,1600,1480,760 (CC
l ₃ ).

NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in (CD ₃ ) ₂ CO: δ -133.0pp
m (d, d, d, J _FF = 21.2Hz, J _FH = 9.1Hz, J _FH = 7.4Hz), δ -13
6.9ppm (d, d, d, J _FF = 21.6Hz, J _FH = 11.4Hz, J _HF H = 7.1Hz)
.

< ¹ Hnmr> δppm from TMS in (CD ₃ ) ₂ CO:
δ 7.90ppm (1H, d, d, J _HF = 11.4Hz, J _HF = 7.4Hz), δ 8.27p
pm (1H, d, d, J _HF = 9.1Hz, J _HF = 7.1Hz).

Elemental analysis: Cl 34.3%, C
Calculated value for ₇ H ₂ BrCl ₃ F ₂ : Cl 34.2
7%.

Then, as in Example 1, 50 g of 95% sulfuric acid
At 40 ° C., 17.5 g of 2-bromo-4,5-difluorobenzotrichloride was added dropwise thereto, and a hydrolysis reaction was carried out for 2 hours. When the same treatment was carried out, 2-bromo-4,5-difluorobenzoic acid was converted to 12 0.6 g (94% yield) was obtained.
m. p. 110.5-111.5 ° C.

Example 6 In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were added. Mol) and 1,2,3-trichloro-4-fluorobenzene under reflux.
0 g (0.1 mol) was added dropwise, followed by a reaction for 30 minutes. When treated in the same manner as in Example 1, 29.9 g of 2,3,4-trichloro-5-fluorobenzotrichloride was obtained.
(62.8% yield) was obtained. m. p. 72-73 ° C,
The purity was 98.7%.

The structure was confirmed by the following analysis.・ IR analysis (neat) (cm ^-1 ): 3060,1590,1470,765 (CC
l ₃ ).

NMR analysis < ¹⁹ Fnmr> δ ppm from CFCl ₃ in (CD ₃ ) ₂ CO: δ -115.0 pp
m (d, J _FH = 8.8Hz).

< ¹ Hnmr> δppm from TMS in (CD ₃ ) ₂ CO:
δ 7.77 ppm (d, J _FH = 8.8 Hz).

Elemental analysis: 67.2% Cl, C
Calculated for ₇ HCl ₆ F: 67.19% Cl.

Next, as in Example 1, 50 g of 95% sulfuric acid was used.
At 40 ° C., 19.9 g of 1,2,3-trichloro-4-fluorobenzotrichloride was added dropwise thereto, and a hydrolysis reaction was carried out for 2 hours. 14.5 g of ro -4- fluorobenzoic acid (95% yield)
Obtained. m. p. 150.0-151 ° C.

[0071]

According to the present invention, a fluorobenzotrichloride compound useful as a pharmaceutical intermediate can be industrially safe and easily obtained from a fluorobenzene compound.

Claims (4)

(57) [Claims] 1. A 2-chloro-4,5-difluorobenzotrichloride. Embedded image 2. A 2,4,5-trifluorobenzotrichloride. Embedded image 3. A 2-bromo-4,5-difluorobenzotrichloride. Embedded image 4. A 2,3,4-trichloro-5-fluorobenzotrichloride. Embedded image