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DESCRIPTION CN113912487A

A kind of synthetic method of 2,5-dihalobenzoic acid

[0001]

technical field

[n0001]

The invention relates to the technical field of preparation of dihalobenzoic acid, and more particularly, to a method for
synthesizing 2,5-dihalobenzoic acid.

[0003]

Background technique

[n0002]

2,5

- Dihalobenzoic acids, such as 5-bromo-2-chlorobenzoic acid, are important intermediates in the synthesis of antidiabetic drugs
dapagliflozin, ipagliflozin and other antiviral drugs and renin inhibitors.

The reported synthetic method raw materials of 5-bromo-2-chlorobenzoic acid at present are roughly divided into the following
three categories, which are directly using 5-bromo-2-chloro-trihalotoluene as a raw material, and using o-chlorotrichlorotoluene
as a raw material. Starting materials and studies with 2-chlorobenzoic acid as starting material.

[n0003]

The first one is to prepare 2,5-dihalobenzoic acid starting from 5-bromo-2-chloro-trihalotoluene as raw material.

For example, patent CN200410057247.3 discloses a method for preparing 2,5-dihalobenzoic acid, which starts from 5-bromo-2-
chlorotrifluorotoluene, heats and hydrolyzes it in oleum, and then adds the reaction solution to The crude product was obtained
by desorption of water in crushed ice, and the crude product was recrystallized to obtain the product.

However, the raw materials of this method are not easy to obtain, which limits its industrial application. In order to solve the
problem of obtaining raw materials in the above-mentioned method, the second one is reported to prepare the desired
compound from o-chlorotrichlorotoluene. For example, patent US20160097744A1 and patent CN107162894A all reported
starting from o-chlorotrichlorotoluene, through different bromination methods, obtained 2-chloro-5-bromo-trichlorotoluene, and
then hydrolyzed to obtain 5-bromo-2-chlorobenzoic acid . The bromination conditions are bromine, or bromination methods such

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as sodium bromide/potassium-sodium/potassium combination, etc., facing non-specific bromination position selectivity,

impurities and products are positional isomers, similar in nature, not easy to separate , affecting product quality. The third kind,
takes 2-chlorobenzoic acid as starting material, and obtains the desired product through bromination. As in the literature
Amalendu B.Gopal Ch.etc. Bromination of halobenzenes and halobenzoicacids. J. Indian Chem. Soc. 1980, 57(6), 640-642. 5-
Bromo-2-chlorobenzoic acid is prepared by using 2-chlorobenzoic acid as a raw material, and using potassium bromate and
sodium bromide systems for bromination respectively. However, the final yield of this synthesis method is extremely low, only
40%. Patent CN108250060A discloses a method for synthesizing 5-bromo-2-chlorobenzoic acid. Using 2-chlorobenzoic acid as
a starting material, 5-bromo-2-chlorobenzoic acid is directly prepared by bromination. The raw materials of this route are easy to
obtain, The process is simple. However, this method is difficult to control the impurity of the brominated product, and the isomers
that are substituted at other positions on the benzene ring. In the application with the publication number of CN107954852A, the
process is completed by using sodium periodate solution as the bromination reagent, but the use of sodium periodate increases
the production cost and is not suitable for industrial production. Patent CN104744227A discloses a kind of preparation method
of 5-bromo-2-chlorobenzaldehyde, which reports that 5-bromo-2 is obtained by monobromination in NBS (N-
bromosuccinimide)/sulfuric acid system - the method of chlorobenzoic acid, the reaction process of this method is simple, the
raw material is easy to obtain, and improves the selectivity of the bromination process of 2-chlorobenzoic acid, but still has
about 10% of 4-bromo-2-chlorobenzoic acid impurities The formation of this impurity is similar to the polarity of the product,
which is difficult to remove by conventional means and affects the quality of the product.

[0006]

SUMMARY OF THE INVENTION

[n0004]

The technical problem to be solved by the present invention is to solve the problems of low bromination selectivity and low
product purity of the existing preparation method of 2,5-dihalobenzoic acid.

[n0005]

The present invention realizes and solves the above-mentioned technical problems through the following technical means:

[n0006]

A kind of synthetic method of 2,5-dihalogenated benzoic acid, comprises the following steps:

[n0007]

(1)According to the mass ratio of 1:1-1:1.2, anthranilic acid and acetic anhydride are mixed, heated to 80-120 ℃ for 3-6 hours,
and after the reaction is detected, it is cooled to 25-40 ℃ naturally, and then the reaction The liquid is poured into deionized
water, fully stirred and hydrolyzed to form a suspension, filtered and dried to obtain 2-acetamidobenzoic acid;

[n0008]

(2)According to the mass ratio of 1:6-1:8, the 2-acetamidobenzoic acid obtained in step (1) is dissolved in acetic acid, bromine is
added dropwise, and the system is maintained at 25-40 ° C. After the detection reaction is complete, the The reaction solution is
poured into deionized water, filtered, washed with water, and dried to obtain 2-acetamido-5-bromobenzoic acid, wherein the
quality of the bromine added dropwise is 1-1.05 times the quality of the 2-acetamidobenzoic acid;

[n0009]

(3)According to the mass ratio of 1:4-1:6, the 2-acetamido-5-bromobenzoic acid obtained in step (2) was added to the aqueous
sodium hydroxide solution in batches, heated at 50-90 ° C, and the reaction was complete after testing After, cooling and
crystallization, filtering, washing with water to obtain 2-amino-5-bromobenzoic acid;

[n0010]

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(4)According to the mass ratio of 1:3-1:5, the 2-amino-5-bromobenzoic acid obtained in step (3) is dissolved in an aqueous
hydrochloric acid solution, cooled to 0-5° C., and then added to an aqueous solution of sodium nitrite. The quality of the sodium
nitrate aqueous solution is 2-2.6 times the quality of the 2-amino-5-bromobenzoic acid. After maintaining the reaction for 1-2
hours, the reaction solution is added to the cuprous chloride solution, and the quality of the cuprous chloride solution is 1.5
times, heat up to 15-40 ° C after the addition, and after the detection reaction is complete, the product is extracted with an
organic solvent, the organic phase is washed with water, dried, and desolubilized to obtain a crude 5-bromo-2-chlorobenzoic
acid, which is recrystallized 2,5-dihalogenated benzoic acid is obtained afterward.

[n0011]

The invention uses a brand new material anthranilic acid as the starting reactant, and due to the strong positioning effect of the
amino group, the bromination mainly occurs in the para-position of the amino group, the bromination selectivity is high, the
reaction conditions are mild, and the product purity can reach more than 99%.

[n0012]

Preferably, in the step (1), the mass of deionized water is 6-10 times the mass of the reaction solution.

[n0013]

Preferably, the drying temperature in the step (1) is 40-65°C.

[n0014]

Preferably, in the step (2), the quality of the deionized water is 6-8 times the quality of the reaction solution.

[n0015]

Preferably, the drying temperature in the step (2) is 40-65°C.

[n0016]

Preferably, the concentration of the sodium hydroxide aqueous solution in the step (3) is 20%.

[n0017]

Preferably, the concentration of the aqueous hydrochloric acid solution in the step (4) is 6M.

[n0018]

Preferably, the drying temperature in the step (4) is 40-65°C.

[n0019]

Preferably, the concentration of the sodium nitrite aqueous solution in the step (4) is 25-30%.

[n0020]

Preferably, the concentration of cuprous chloride in the step (4) is 20%.

[n0021]

The present invention has the following beneficial effects:

[n0022]

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1、The invention uses a brand new material anthranilic acid as the starting reactant. Due to the strong positioning effect of the
amino group, the bromination selectivity is high, the reaction conditions are mild, and the product purity can reach more than
99%.

[n0023]

2、The preparation method of the invention has simple process steps, easy purification of the product, large-scale synthesis of
5-bromo-2-chlorobenzoic acid, and high industrialization development prospect.

[0027]

Description of drawings

[n0024]

Fig. 1 is the high-performance liquid chromatogram of 2,5-dihalobenzoic acid prepared by Invention Example 1;

[n0025]

FIG. 2 is a hydrogen nuclear magnetic spectrum of 2,5-dihalogenated benzoic acid prepared in Example 1 of the invention.

[0030]

detailed description

[n0026]

In order to make the purposes, technical solutions and advantages of the embodiments of the present invention clearer, the
technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to
the accompanying drawings and the embodiments of the present invention. Obviously, the described embodiments These are
some embodiments of the present invention, but not all embodiments.

Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without
creative efforts shall fall within the protection scope of the present invention.

[n0027]

The test materials and reagents used in the following examples can be obtained from commercial sources unless otherwise
specified.

[n0028]

If the specific technology or condition is not indicated in the embodiment, it can be carried out according to the technology or
condition described in the literature in this field or according to the product specification.

[n0029]

Example 1

[n0030]

A kind of synthetic method of 2,5-dihalogenated benzoic acid, synthetic process is shown in following formula:

[n0032]

Include the following steps:

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[n0033]

(1)Mix 60g of anthranilic acid with 60g of acetic anhydride, heat to 80°C and react for 4h. After confirming that the reaction is
complete by thin layer chromatography or liquid phase detection, cool to 40°C naturally, then pour the reaction solution into
deionized water, deionized The water quality is 6 times the quality of the reaction solution, fully stirred and hydrolyzed to form a
suspension, filtered and dried at 50°C to obtain 2-acetamidobenzoic acid;

[n0034]

(2)Be 1:6 according to mass ratio, the 2-acetamidobenzoic acid obtained in step (1) is dissolved in acetic acid, drip bromine, the
bromine quality that drips is 1 times of 2-acetamidobenzoic acid quality, Maintain the system at 40°C, after confirming that the
reaction is complete by thin-layer chromatography or liquid phase detection, pour the reaction solution into deionized water, and
the quality of deionized water is 6 times that of the reaction solution. 2-Acetylamino-5-bromobenzoic acid;

[n0035]

(3)According to the mass ratio of 1:4, the 2-acetamido-5-bromobenzoic acid obtained in step (2) was added in batches to the
aqueous sodium hydroxide solution with a concentration of 20%, heated to 50° C., and subjected to thin-layer chromatography.
Or after the liquid phase detection confirms that the reaction is complete, the temperature is lowered for crystallization, filtered,
and washed with water to obtain 2-amino-5-bromobenzoic acid;

[n0036]

(4)According to the mass ratio of 1:3, the 2-amino-5-bromobenzoic acid obtained in step (3) was dissolved in an aqueous
hydrochloric acid solution, cooled to 5°C, and then added to a 25% aqueous solution of sodium nitrite with a concentration of
25% sodium nitrite. The quality of the aqueous solution is twice the quality of 2-amino-5-bromobenzoic acid. After maintaining
the reaction for 1 hour, the reaction solution is added to the cuprous chloride solution with a concentration of 20%. The quality of
the cuprous chloride solution is 1.5 times the mass of the reaction solution. After the addition was completed, the temperature
was raised to 40 ° C. After the completion of the reaction was confirmed by thin-layer chromatography or liquid phase detection,
the product was extracted with an organic solvent. The organic phase was washed with water, dried at 50 ° C, and desolvated to
obtain 5-bromo-2-chloro The crude product of benzoic acid is recrystallized to obtain a fine product of 2,5-dihalobenzoic acid.

[n0037]

The 2,5-dihalogenated benzoic acid fine product prepared in this example is subjected to HPLC detection, and the detection
result is found, and the detection result is shown in Figure 1, it can be found that the purity of the 2,5-dihalogenated benzoic acid
prepared in this embodiment is greater than 99%.

[n0038]

The 2,5-dihalogenated benzoic acid prepared in this example was detected by hydrogen nuclear magnetic spectrum, and the
detection result was shown in FIG. 2 .

[n0039]

Example 2

[n0040]

A kind of synthetic method of 2,5-dihalogenated benzoic acid, comprises the following steps:

[n0041]

(1)Mix 60g of anthranilic acid with 66g of acetic anhydride, heat to 95°C and react for 5h. After confirming that the reaction is
complete by thin layer chromatography or liquid phase detection, cool to 40°C naturally, then pour the reaction solution into

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deionized water, deionized The water quality is 8 times the quality of the reaction solution, fully stirred and hydrolyzed to form a
suspension, filtered and dried at 50°C to obtain 2-acetamidobenzoic acid;

[n0042]

(2)Be 1:7 according to mass ratio, the 2-acetamidobenzoic acid obtained in step (1) is dissolved in acetic acid, drip bromine, the
bromine quality that drips is 1.05 times of 2-acetamidobenzoic acid quality, Maintain the system at 40°C, after confirming that
the reaction is complete by thin-layer chromatography or liquid phase detection, pour the reaction solution into deionized water,
the quality of deionized water is 8 times that of the reaction solution, filter, wash with water, and dry at 50°C to obtain 2-
Acetylamino-5-bromobenzoic acid;

[n0043]

(3)According to the mass ratio of 1:5, the 2-acetamido-5-bromobenzoic acid obtained in step (2) was added in batches to the
aqueous sodium hydroxide solution with a concentration of 20%, heated to 50 ° C, and subjected to thin-layer chromatography.
Or after the liquid phase detection confirms that the reaction is complete, the temperature is lowered for crystallization, filtered,
and washed with water to obtain 2-amino-5-bromobenzoic acid;

[n0044]

(4)According to the mass ratio of 1:4, the 2-amino-5-bromobenzoic acid obtained in step (3) was dissolved in an aqueous
hydrochloric acid solution, cooled to 5°C, and then added to a 26% aqueous solution of sodium nitrite with a concentration of
26% sodium nitrite. The quality of the aqueous solution is twice the quality of 2-amino-5-bromobenzoic acid. After maintaining
the reaction for 2 hours, the reaction solution is added to the cuprous chloride solution with a concentration of 20%. The quality
of the cuprous chloride solution is 1.5 times the mass of the reaction solution. After the addition was completed, the temperature
was raised to 40 ° C. After the completion of the reaction was confirmed by thin-layer chromatography or liquid phase detection,
the product was extracted with an organic solvent. The organic phase was washed with water, dried at 50 ° C, and desolvated to
obtain 5-bromo-2-chloro The crude product of benzoic acid is recrystallized to obtain a fine product of 2,5-dihalobenzoic acid.

[n0045]

The 2,5-dihalobenzoic acid product prepared in this example was tested by HPLC, and the detection result showed that the
purity of the 2,5-dihalobenzoic acid prepared in this example was greater than 99%.

[n0046]

Example 3

[n0047]

A kind of synthetic method of 2,5-dihalogenated benzoic acid, comprises the following steps:

[n0048]

(1)Mix 60g of anthranilic acid with 72g of acetic anhydride, heat to 120℃ for 6h, after confirming that the reaction is complete by
thin layer chromatography or liquid phase detection, cool to 40℃ naturally, then pour the reaction solution into deionized water,
deionized The water quality is 10 times the quality of the reaction solution, fully stirred and hydrolyzed to form a suspension,
filtered and dried at 50°C to obtain 2-acetamidobenzoic acid;

[n0049]

(2)Be 1:8 according to mass ratio, the 2-acetamidobenzoic acid obtained in step (1) is dissolved in acetic acid, drip bromine, the
bromine quality that drips is 1.05 times of 2-acetamidobenzoic acid quality, Maintain the system at 40°C, after confirming that
the reaction is complete by thin-layer chromatography or liquid phase detection, pour the reaction solution into deionized water,
the quality of deionized water is 8 times that of the reaction solution, filter, wash with water, and dry at 50°C to obtain 2-
Acetylamino-5-bromobenzoic acid;
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[n0050]

(3)According to the mass ratio of 1:6, the 2-acetamido-5-bromobenzoic acid obtained in step (2) was added in batches to the
aqueous sodium hydroxide solution with a concentration of 20%, heated to 50 ° C, and subjected to thin-layer chromatography.
Or after the liquid phase detection confirms that the reaction is complete, the temperature is lowered for crystallization, filtered,
and washed with water to obtain 2-amino-5-bromobenzoic acid;

[n0051]

(4)According to the mass ratio of 1:5, the 2-amino-5-bromobenzoic acid obtained in step (3) was dissolved in an aqueous
hydrochloric acid solution, cooled to 5° C., and then added to a 28% aqueous sodium nitrite solution with a concentration of 28%
sodium nitrite. The quality of the aqueous solution is 2.6 times the quality of 2-amino-5-bromobenzoic acid. After maintaining the
reaction for 2 hours, the reaction solution is added to the cuprous chloride solution with a concentration of 20%. The quality of
the cuprous chloride solution is 1.5 times the mass of the reaction solution. After the addition was completed, the temperature
was raised to 40 ° C. After the completion of the reaction was confirmed by thin-layer chromatography or liquid phase detection,
the product was extracted with an organic solvent. The organic phase was washed with water, dried at 50 ° C, and desolvated to
obtain 5-bromo-2-chloro The crude product of benzoic acid is recrystallized to obtain a fine product of 2,5-dihalobenzoic acid.

[n0052]

The 2,5-dihalobenzoic acid product prepared in this example was tested by HPLC, and the detection result showed that the
purity of the 2,5-dihalobenzoic acid prepared in this example was greater than 99%.

[n0053]

Comparative Example 1

[n0054]

Synthesize 5-bromo-2-chlorobenzoic acid with 2-chlorobenzoic acid using sodium bromide and potassium bromate for oxidative
bromination, and the specific operations are as follows:

[n0055]

Add 94 g of 2-chlorobenzoic acid and 1120 mL of sulfuric acid into the reaction flask in turn, stir to dissolve, add 110 g of NBS,
heat to 40-50 ° C, and stir until the reaction is complete; add the reaction droplets into ice water, stir for 30 min, and filter to
obtain Crude white.

[n0056]

Under the conditions of this comparative example, 5-bromo-2-chlorobenzoic acid was prepared, and the by-product 3-bromo-2-
chlorobenzoic acid was also produced. Low purity.

[n0057]

The above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them;
although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill
in the art should understand that: The recorded technical solutions are modified, or some technical features thereof are
equivalently replaced; and these modifications or replacements do not make the essence of the corresponding technical
solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

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