2/4/22, 2:44 PM JP2021195344A - Method for producing 5-bromo-2-halogenated benzoic acid - Google Patents

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JP2021195344

Method for producing 5-bromo-2-halogenated benzoic acid

Abstract
JP2021195344A
PROBLEM TO BE SOLVED: To provide a method for producing 5-bromo-2-halogenated benzoic acid
Japan
having high production efficiency.

SOLUTION: In the presence of sulfuric acid, a 2-halogenated benzoic acid represented by the formula
(I) and a brominated hydantin are brought into contact with each other to contain a 5-bromo-2- Download PDF
Find Prior Art
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halogenated benzoic acid represented by the formula (II). 1 A method for producing 5-bromo-2-
halogenated benzoic acid, which comprises obtaining a mixture.
Other languages: Japanese

Inventor: 雅彦 関

(X is Cl, Br, F or I)

[Selection diagram] None Worldwide applications

Application JP2020103937A events

2020-06-16 Application filed by 株式会社トクヤマ

2021-12-27 Publication of JP2021195344A

Status Pending

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External links: Espacenet, Global Dossier, Discuss

Claims (3) Hide Dependent

1. A first mixture containing 5-bromo-2-halogenated benzoic acid represented by the following formula (II) by contacting 2-halogenated benzoic acid represented by the
following formula (I) with brominated hydantin in the presence of sulfuric acid. Method for producing 5-bromo-2-halogenated benzoic acid, including obtaining:

In the formula (I), X is a halogen element selected from the group consisting of Cl, Br, F and I.

In the formula (II), X is the same as X in the formula (I).

2. The 5-bromo-2-halogen according to claim 1, wherein the amount of the brominated hydantoin with respect to 1 mol of the 2-halogenated benzoic acid
represented by the formula (I) is 0.1 mol or more and 1.0 mol or less. A method for producing benzoic acid.

3. The method for producing 5-bromo-2-halogenated benzoic acid according to claim 1 or 2, wherein the amount of the sulfuric acid with respect to 1 g of the 2-
halogenated benzoic acid represented by the formula (I) is 1 mL or more and 10 mL or less.

Description

The present invention relates to a method for producing 5-bromo-2-halogenated benzoic acid.

Dapagliflozin represented by the following formula (VI), eltzgliflozin represented by the following formula (VII), and empagliflozin represented by the following formula
(VIII) are active ingredients of an antidiabetic drug (Non-Patent Document 1).

The 5-bromo-2-chlorobenzoic acid represented by the following formula (III) is used as an intermediate for synthesizing dapagliflozin, ertzgliflozin, and empagliflozin.

As a method for producing 5-bromo-2-chlorobenzoic acid, a plurality of methods for synthesizing by reacting 2-chlorobenzoic acid represented by the following formula
(IV) with a brominating agent are disclosed.

In Patent Document 1, 5-bromo-2-chlorobenzoic acid is synthesized by dropping concentrated sulfuric acid into a mixture of 2-chlorobenzoic acid, sodium bromide, and
an acetic acid solution of sodium periodate. It is stated that it should be done.

Patent Document 2 describes the synthesis of 5-bromo-2-chlorobenzoic acid by reacting 2-chlorobenzoic acid with NBS (N-bromosuccinimide) in the presence of sulfuric
acid and DCM (dichloromethane). Is described.

Chinese Patent Application Publication No. 1079548552

Chinese Patent Application Publication No. 110105193

An object of the present invention is to provide a method for producing 5-bromo-2-halogenated benzoic acid having high production efficiency.

According to one embodiment, the 2-halogenated benzoic acid represented by the following formula (I) and the brominated hydantin are brought into contact with each
other in the presence of sulfuric acid to bring the 5-bromo-2-halogenated benzoic acid represented by the following formula (II) into contact with each other. A method for
producing 5-bromo-2-halogenated benzoic acid, which comprises obtaining a first mixture containing an acid, is provided.

In formula (I), X is a halogen element selected from the group consisting of Cl, Br, F and I.

In formula (II), X is identical to X in formula (I).

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2/4/22, 2:44 PM JP2021195344A - Method for producing 5-bromo-2-halogenated benzoic acid - Google Patents
According to the present invention, there is provided a method for producing 5-bromo-2-halogenated benzoic acid having high production efficiency.

In the methods described in Patent Documents 1 and 2, it is necessary to use an expensive reagent as a halogenating agent. In addition, the methods described in Patent
Documents 1 and 2 have room for improvement in the conversion rate of 2-chlorobenzoic acid. Therefore, there is a demand for a method for producing 5-bromo-2-
halogenated benzoic acid, which is cheaper and has higher production efficiency.

As a result of diligent research by the present inventors, it has been found that the bromination of 2-halogenated benzoic acid can be efficiently promoted by using
brominated hydantoin as an odorant in the presence of sulfuric acid. The reason for this is considered to be that high reactivity due to the resonance structure mediated
by the heteroatom and high stereoselectivity due to the steric bulkiness are exhibited. In addition, brominated hydantoin is a relatively inexpensive reagent. Therefore,
according to this method, 5-bromo-2-halogenated benzoic acid can be obtained at a relatively low cost and in a high yield.

The details of this method will be described below.

2-Halogenated benzoic acid is represented by the following formula (I).

In the formula (I), X is a halogen element selected from the group consisting of Cl, Br, F and I. X is preferably Cl. That is, the production method according to the
embodiment is particularly suitable as a production method for 5-bromo-2-chlorobenzoic acid using 2-chlorobenzoic acid as a substrate.

As the 2-halogenated benzoic acid, an industrially available one may be used, or a synthetic one may be used.

Brominated hydantoin is a compound having a hydantoin skeleton containing a bromo group. The brominated hydantoin acts as a brominating agent. Examples of the
brominated hydantoin include 1,3-dibromo-5,5-dimethylhydantoin, 1-bromo-3-chloro-5,5-dimethylhydantoin, and 1-chloro-3-bromo-5,5-dimethyl. At least one selected from
the group consisting of hydantoin is used. As the brominated hydantoin, it is preferable to use 1,3-dibromo-5,5-dimethylhydantoin. 1,3-Dibromo-5,5-dimethylhydantoin is
represented by the following formula (V).

The amount of brominated hydantoin with respect to 2-halogenated benzoic acid is not particularly limited as long as it is sufficient for bromination. The amount of
brominated hydantin with respect to 1 mol of 2-halogenated benzoic acid represented by the formula (I) is, for example, 0.1 mol or more and 1.0 mol or less, preferably
0.2 mol or more and 0.8 mol or less. It is more preferably 0.4 mol or more and 0.6 mol or more, and further preferably 0.45 mol or more and 0.55 mol or less.

Sulfuric acid acts as an oxidant and reaction solvent. That is, in the bromination of an aromatic compound, the bromine cation (Br + ) becomes an active species and
binds to the benzene ring. Sulfuric acid promotes the production of bromine cations from brominated hydantoin. In the production method according to the embodiment,
since sulfuric acid and brominated hydridein are used in combination, bromination of 2-halogenated benzoic acid can be efficiently performed without using an oxidizing
agent such as sodium periodate. ..

It is preferable to use sulfuric acid having a high concentration in order to avoid mixing of water, and it is preferable to use concentrated sulfuric acid having a
concentration of 90% by mass or more. When water is mixed in the reaction system, the reactivity between 2-halogenated benzoic acid and brominated hydantoin may
decrease. The concentration of sulfuric acid is preferably 96% by mass or more, more preferably 98% by mass or more. The upper limit of the concentration of sulfuric
acid is 100% by mass. Oleum sulfuric acid may be used as the sulfuric acid.

Sulfuric acid is preferably used in a sufficient amount as an oxidizing agent and a reaction solvent. 1 mL or more may be used with respect to 1 g of 2-halogenated
benzoic acid, and 2 mL or more is more preferable. There is no particular upper limit to the amount of sulfuric acid, but it is 10 mL or less according to one example and 5
mL or less according to another example with respect to 1 g of 2-halogenated benzoic acid.

The contact between 2-halogenated benzoic acid and brominated hydantoin is not particularly limited as long as it is carried out in the presence of sulfuric acid. Sulfuric
acid may be added to this mixture after mixing 2-halogenated benzoic acid and brominated hydantine, or 2-halogenated benzoic acid and sulfuric acid may be mixed and
then brominated hydantine is added to this mixture. Alternatively, 2-halogenated benzoic acid may be added to the mixture after mixing the brominated hydantin and
sulfuric acid.

Preferably, after mixing 2-halogenated benzoic acid with sulfuric acid, brominated hydantoin is added to this mixture. At this time, 2-halogenated benzoic acid is
preferably dissolved in sulfuric acid.

The reaction between 2-halogenated benzoic acid and brominated hydantoin in the presence of sulfuric acid is preferably carried out at a temperature in the range of −5 °
C. or higher and 60 ° C. or lower, and preferably in the range of 0 ° C. or higher and 40 ° C. or lower. It is more preferable to be carried out in. Further, these reaction times
are preferably 1 hour or more and 72 hours or less, and more preferably 3 hours or more and 24 hours or less.

In order to further increase the production efficiency, the contact between the 2-halogenated benzoic acid and the brominated hydantoin in the presence of sulfuric acid is
preferably carried out in the reaction solvent. The amount of the reaction solvent for 1 g of 2-halogenated benzoic acid is, for example, 1 mL or more and 20 mL or less,
preferably 3 mL or more and 15 mL or less.

As the reaction solvent, for example, at least one selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane is
used. When 2-chlorobenzoic acid is used as the substrate, it is particularly preferable to use methylene chloride as the reaction solvent.

More preferred embodiments for promoting the bromoization reaction of 2-halogenated benzoic acid are as follows. First, 2-halogenated benzoic acid is dissolved in
sulfuric acid and a reaction solvent to prepare a 2-halogenated benzoic acid solution. Brominated hydantoin is added to this 2-halogenated benzoic acid solution at room
temperature, and the mixture is stirred at room temperature.

By the above method, a first mixture containing 5-bromo-2-halogenated benzoic acid can be obtained. 5-bromo-2-halogenated benzoic acid is represented by the
following formula (II).

In formula (II), X is the same as X in formula (I). As mentioned above, X is preferably Cl. 5-Bromo-2-chlorobenzoic acid in which X is Cl can be used as a synthetic material
for dapagliflozin, ertzgliflozin, and empagliflozin, which are active ingredients of antidiabetic agents.

The reaction of 2-halogenated benzoic acid with brominated hydantoin in the presence of sulfuric acid is preferably terminated by adding a quench solution to the first
mixture. As the quenching liquid, water, an organic solvent, or a mixed solvent thereof can be used. As the organic solvent, the above-mentioned reaction solvent can be
used. The amount of the quench solution is, for example, 3 mL or more and 60 mL or less, preferably 6 mL or more and 30 mL or less, relative to 1 g of 2-halogenated
benzoic acid. The temperature of the first mixture when the quench liquid is added is preferably in the range of 0 ° C. or higher and 60 ° C. or lower, and more preferably in
the range of 10 ° C. or higher and 40 ° C. or lower.

The organic layer is extracted from the first mixture to which the quench solution is added and concentrated under reduced pressure to obtain a solid substance
containing crystals of unpurified 5-bromo-2-halogenated benzoic acid.

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2/4/22, 2:44 PM JP2021195344A - Method for producing 5-bromo-2-halogenated benzoic acid - Google Patents
The obtained solid substance may contain 3-bromo-2-halogenated benzoic acid, which is an isomer of 5-bromo-2-halogenated benzoic acid. The proportions of 5-bromo-
2-halogenated benzoic acid and 3-bromo-2-halogenated benzoic acid in the solid can be confirmed by High Performance Liquid Chromatography (HPLC).

The analysis conditions of HPLC are as follows, for example.

HPLC analysis conditions:

Sample concentration: 0.5% THF

Injection volume: 5 μL

Detection wavelength: 254nm

Flow rate: 1.0 mL / min

Column temperature: 30 ° C

Mobile phase: 30-100% acetonitrile / 0.1% phosphoric acid (0-15 min)

Filler: X Bridge C18 5 μm (4.6 x 150 mm)

Retention time: Raw material: 5.106 min; 4-bromo form: 7.205 min; 2-bromo form: 6.884 min

The unpurified crystals of 5-bromo-2-halogenated benzoic acid obtained by the above method are preferably purified. The purification method is, for example, taking out a
solid containing 5-bromo-2-halogenated benzoic acid from the first mixture and dissolving the taken out solid of 5-bromo-2-halogenated benzoic acid in a purification
solvent. The first solution is cooled to obtain a precipitate of 5-bromo-2-halogenated benzoic acid.

That is, the crystals of unpurified 5-bromo-2-halogenated benzoic acid are dissolved in a purified solvent and then reprecipitated to obtain purified crystals of 5-bromo-2-
halogenated benzoic acid. Be done. The obtained crystals are preferably dried under reduced pressure at a temperature of 40 ° C. or higher and 70 ° C. or lower.

Examples of the purification solvent include methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl
acetate, isopropyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran (THF), and the like. At least one selected from the group consisting of 2-
methyltetratetratransferase, N, N-dimethylformamide (DMF), dimethylacetamide (DMA), acetic acid, and water is used.

Toluene is preferably used as the purification solvent. By using toluene, the proportion of 5-bromo-2-halogenated benzoic acid in the crystals can be increased.

The amount of the purification solvent is not particularly limited. According to one example, the amount of the purified solvent per 1 g of the solid matter is 0.5 mL or
more and 20 mL or less, and according to another example, 0.7 mL or more and 3 mL or less.

After cooling the first solution, it is preferable to stir for 10 hours or more and 30 hours or less to reprecipitate the crystals of 5-bromo-2-halogenated benzoic acid. The
temperature at which the crystals of 5-bromo-2-halogenated benzoic acid are reprecipitated is, for example, −10 ° C. or higher and 100 ° C. or lower, preferably 5 ° C. or
higher and 50 ° C. or lower.

When toluene is used as the purification solvent, the toluene is heated to 50 ° C. or higher to dissolve the solid substance to obtain a first solution, and then cooled to 30 °
C. or lower to crystallize 5-bromo-2-halogenated benzoic acid. Is preferably reprecipitated. As a result, crystals of 5-bromo-2-halogenated benzoic acid with higher purity
can be obtained.

The upper limit of the heating temperature of toluene is, for example, 80 ° C. or lower. The lower limit of the cooling temperature of the first solution is, for example, 0 ° C.
or higher.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are specific examples, and the present invention
is not limited thereto.

<Example 1>

5-Bromo-2-chlorobenzoic acid was synthesized by the following method.

First, 1.00 g (6.39 mmol) of 2-chlorobenzoic acid was dissolved in 3 mL of sulfuric acid and 8 mL of methylene chloride to prepare a 2-chlorobenzoic acid solution. This
2-fluorobenzoic acid solution was obtained by adding 0.91 g (3.85 mmol) of 1,3-dibromo-5,5-dimethylhydantoin over 1 minute while maintaining the temperature at 20 °
C. The mixture was stirred at 20 ° C. for 20 hours.

A mixed solvent of 10 mL of water and 10 mL of methylene chloride was added to the stirred mixture, and the mixture was separated into two layers, an organic layer and
an aqueous layer. The organic layer was extracted and concentrated under reduced pressure to give 1.8 g of solid. When the ratio of 5-bromo-2-chlorobenzoic acid and 3-
bromo-2-chlorobenzoic acid in the solid substance was confirmed by HPLC, 5-bromo-2-chlorobenzoic acid: 3-bromo-2-chloro was confirmed. Benzoic acid = 7: 1. The
conversion rate was 100%.

The obtained solid was dissolved in 5.4 mL of toluene at a temperature of 70 ° C. to obtain a first solution. The first solution was cooled to 20 ° C. and then stirred for 19
hours while maintaining the temperature at 20 ° C. to reprecipitate the crystals. The reprecipitated crystals were taken out and dried under reduced pressure at a
temperature of 50 ° C. to obtain a solid substance containing the purified 5-bromo-2-fluorobenzoic acid crystals. The amount of crystals after purification was 1.05 g, and
the yield was 70%. When the ratio of 5-bromo-2-chlorobenzoic acid and 3-bromo-2-chlorobenzoic acid in the solid substance was confirmed by HPLC, only 5-bromo-2-
chlorobenzoic acid was contained.

<Comparative Example 1>

Performed except that 1.27 g (7.14 mmol) of NBS (N-bromosuccinimide) was used in place of 0.91 g (3.85 mmol) of 1,3-dibromo-5,5-dimethylhydantoin. 5-Bromo-2-
chlorobenzoic acid was synthesized in the same manner as described in Example 1. When confirmed by HPLC, the conversion rate was 80.9%.

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