CN113321577 Preparation Method of 5-Bromo-2-Chlorobenzoic Acid

3/23/22, 2:55 PM CN113321577 Preparation method of 5-bromo-2-chlorobenzoic acid
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1. CN113321577 - PREPARATION METHOD OF 5-

BROMO-2-CHLOROBENZOIC ACID
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The preparation method of 5-bromo-2-chlorobenzoic

acid
technical field
The invention relates to a preparation method of 5-bromo-2-chlorobenzoic acid, and belongs to the field
of chemical synthesis.
Background technique
5-Bromo-2-chlorobenzoic acid is widely used, such as intermediates or raw materials for synthetic drugs
or other chemical products, for example, dapagliflozin is a type 2 sodium-glucose cooperating protein ( SGLT-
2), which works by inhibiting the sodium-glucose cooperating protein (a protein in the kidney that enables
glucose to be reabsorbed into the blood), allowing excess glucose to be excreted through the urine without
increasing insulin. It improves blood sugar control under the condition of secretion. Compared with traditional
hypoglycemic drugs, it does not cause adverse reactions such as hypoglycemia and weight gain, so it becomes
the first choice drug for the treatment of diabetes. At present, it is mainly based on 5-bromo-2-chlorobenzoic
acid. As a starting material for the synthesis of dapagliflozin.
At present, the preparation process of 5-bromo-2-chlorobenzoic acid mainly includes: (1) using 2-
chlorotrichlorotoluene as the starting material, and preparing 5-bromo-2-chlorobenzoic acid through processes
such as hydrolysis in a strongly acidic medium, Such as the route shown in the reaction formula 1 disclosed in
patent document CN105622382A), this type of process has defects such as high raw material cost,
complicated operation, many strong acid waste water, and unenvironmental protection; (2) using 2-
chlorobenzoic acid as a raw material, through 5-bromo-2-chlorobenzoic acid is prepared by bromination of
bromination reagent, such as the route shown in reaction formula 2 disclosed by CN110590541A and
CN110105193A, and the literature [Journal of the Indian Chemical Society, 1980, vol.57, #6, p. .640-642] the
route shown in the disclosed reaction formula 3, this type of technology is easy to produce the by-products that
are close to the target product properties, there are defects such as high cost, many by-products, and the
process of the reaction formula 3 is prone to produce a large amount of oxygen , there are also greater security
risks.

SUMMARY OF THE INVENTION
The invention provides a preparation method of 5-bromo-2-chlorobenzoic acid, which has the advantages 
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN336087437&_cid=P21-L13CU6-73741-1 1/7
of simple process, high safety, cheap and easily available raw materials, low cost and high yield and purity of
5-bromo-2-chlorobenzoic acid , which can effectively overcome the defects of the prior art.
The invention provides a preparation method of 5-bromo-2-chlorobenzoic acid, comprising: (1)
contacting 2-chlorobenzonitrile with a brominating reagent to carry out a bromination reaction to prepare 5-
bromo-2-chlorobenzonitrile (2) make 5-bromo-2-chlorobenzonitrile carry out hydrolysis reaction in the
presence of alkali, generate 5-bromo-2-chlorobenzoate; Then make the 5-bromo-2-chlorobenzoic acid The salt
reacts with the protonic acid to produce 5-bromo-2-chlorobenzoic acid.
According to an embodiment of the present invention, the brominating reagent includes bromine, N-
bromosuccinimide, dibromohydantoin, phosphorus tribromide, phosphorus oxytribromide, and pyridine
perbromide hydrobromide , at least one of tetrabromocyclic ketone and tetrabutylammonium bromide.
According to an embodiment of the present invention, the molar ratio of the 2-chlorobenzonitrile to the
bromination reagent is 1:(0.5-3.0).
According to an embodiment of the present invention, the bromination reaction is carried out in a solvent,
and meets: the mass-volume ratio of the 2-chlorobenzonitrile to the solvent is 1:(5.0-10.0); and/or, the The
solvent includes at least one of dichloromethane, 1.2-dichloroethane, chloroform, carbon tetrachloride,
acetonitrile, methyl tert-butyl ether, tetrahydrofuran, ethanol, and ethyl acetate.
According to an embodiment of the present invention, the conditions for the bromination reaction are: the
reaction temperature is 0°C to 100°C, and the reaction time is 3-24 hours.
According to an embodiment of the present invention, in step (2), the molar ratio of the 5-bromo-2-
chlorobenzonitrile to the base is 1:(1.0-5.0); and/or, the base includes inorganic Base, the inorganic base
includes at least one of sodium hydroxide, potassium hydroxide, potassium dihydrogen phosphate, potassium
carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium
hydrogen phosphate.
According to an embodiment of the present invention, the conditions of the hydrolysis reaction are as
follows: the reaction temperature is 30°C to 150°C, and the reaction time is 2 to 24 hours.
According to an embodiment of the present invention, step (2) includes: after the hydrolysis reaction is
completed, adding the protonic acid to the system to make the system acidic, so as to make the 5-bromo-2-
chlorobenzoate salt Contact reaction with protonic acid.
According to an embodiment of the present invention, the molar ratio of the 5-bromo-2-chloroformate to
the protonic acid is 1:(2.0-10.0); and/or, the protonic acid includes sulfuric acid, hydrochloric acid, At least
one of nitric acid, hydrobromic acid, and phosphoric acid.
According to an embodiment of the present invention, the conditions for the contact reaction between the
5-bromo-2-chlorobenzoate and the protonic acid are: the reaction temperature is -10°C to 100°C, and the
reaction time is 2 to 12 hours.
In the present invention, 2-chlorobenzonitrile is used as the starting material, and the strong positioning
effect of the cyano group is utilized to suppress the generation of by-products during the bromination reaction,
and to generate 5-bromo-2-chlorobenzene with high selectivity. Nitrile, and then use the characteristics of 5-
bromo-2-chlorobenzonitrile to be easily hydrolyzed to make it hydrolyzed in an alkaline medium to generate
5-bromo-2-chlorobenzoate, and then make 5-bromo-2-chlorobenzene The formate is contacted with the
protonic acid, and after being freed in an acidic medium, highly selective 5-bromo-2-chlorobenzoic acid is
obtained, and the yield and purity of the 5-bromo-2-chlorobenzoic acid are significantly improved; at the same
time, the present invention The preparation process route of the invention is short, the process is simple, the
operation is easy, the raw materials are cheap and easy to obtain, the cost is low, and a large amount of gas is
not generated during the preparation process of the invention, which is more safe and environmentally
friendly, and has important practical significance for industrial application.
Description of drawings
Fig. 1 and Fig. 2 are respectively the hydrogen nuclear magnetic resonance spectrum ( 1 HNMR) of 5-
bromo-2-chlorobenzoic acid product in an embodiment of the present invention (wherein Fig. 2 is an enlarged
view);
Fig. 3 is the mass spectrum of 5-bromo-2-chlorobenzoic acid product in one embodiment of the present
invention.
detailed description
In order for those skilled in the art to better understand the solution of the present invention, the present
invention is further described in detail below. The specific embodiments listed below are only to describe the
principles and features of the present invention, and the examples are only used to explain the present
invention, and do not limit the scope of the present invention. Based on the embodiments of the present
invention, all other implementations obtained by those of ordinary skill in the art without creative work fall

within the protection scope of the present invention.
The preparation method of 5-bromo-2-chlorobenzoic acid provided by the present invention comprises:
(1) contacting 2-chlorobenzonitrile with a brominating reagent to carry out a bromination reaction to obtain 5-
bromo-2-chlorobenzonitrile; ( 2) make 5-bromo-2-chlorobenzonitrile carry out hydrolysis reaction in the
presence of alkali, generate 5-bromo-2-chlorobenzoate; then make 5-bromo-2-chlorobenzoate and protic acid
Contact reaction to produce 5-bromo-2-chlorobenzoic acid.
In the above-mentioned preparation process, taking 2-chlorobenzonitrile as starting material, the chloro
group is the ortho-para-positioning group at the 5th position on the 2-chlorobenzonitrile, and the cyano group
is the meta-positioning group at the 5th position on the 2-chlorobenzonitrile And it has a strong positioning
effect. During the bromination reaction, the bromination selectivity of the 5-position on 2-chlorobenzonitrile
can be increased, the production of by-products can be suppressed, and a highly selective 5-bromo-2-
chlorobenzonitrile can be obtained. , and then ensure the highly selective synthesis of 5-bromo-2-
chlorobenzoic acid. The research results show that the yield of 5-bromo-2-chlorobenzoic acid is as high as
80% or more, such as 80% to 90%. The chromatographic purity (HPLC purity) is as high as 99% or more.
In some embodiments, the brominating reagent includes bromine, N-bromosuccinimide,
dibromohydantoin, phosphorus tribromide, phosphorus oxytribromide, pyridine perbromide hydrobromide,
tetrabromocyclic At least one of ketone and tetrabutylammonium bromide.
According to the research of the present invention, relatively speaking, if the consumption of the
brominating reagent is too small, the conversion rate of 2-chlorobenzonitrile is low, and if the consumption of
the brominating reagent is too much, the generation of by-products will be caused to a certain extent. Taking
these factors into consideration, the molar ratio of 2-chlorobenzonitrile to the brominating reagent is 1:(0.5-
3.0), such as 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3 or A range consisting of any two of them. Further, the
consumption of the brominating reagent preferably satisfies: in terms of the effective bromine atoms that can
be substituted to 2-chlorobenzonitrile, the molar ratio of the brominating reagent to 2-chlorobenzonitrile is (1
～1.5): 1, for example 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, or a range of any two therein, for example, in some
embodiments, the brominating reagent is N-bromo Succinimide and/or bromine (one N-bromosuccinimide or
bromine can provide an effective bromine atom), its molar ratio to 2-chlorobenzonitrile is (1～1.1.5 ): 1; In
other embodiments, the brominating reagent is dibromohydantoin (one dibromohydantoin can provide two
effective bromine atoms that can be substituted to 2-chlorobenzonitrile), which is combined with 2-
chlorobenzene The molar ratio of nitrile is 1:(0.5-0.75), for example, 1:0.51.
Under normal circumstances, the bromination reaction is carried out in a solvent, and the amount of the
solvent can be controlled as follows: the mass volume ratio of 2-chlorobenzonitrile to the solvent is 1: (5.0～
10.0), and the solvent used can be an organic solvent, preferably including two At least one of methyl chloride,
1.2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, methyl tert-butyl ether, tetrahydrofuran,
ethanol, and ethyl acetate, the use of this solvent is not only conducive to the efficiency of the bromination
reaction , and it is beneficial to remove the solvent from the product system by means of vacuum distillation
and the like after the reaction is completed, thereby simplifying the operation.
Further, the conditions of the bromination reaction can be: the reaction temperature (referred to as the
first reaction temperature) is 0°C to 100°C, such as 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C ℃, 80
℃, 90 ℃, 100 ℃ or the range of any two of them, generally preferably 10-30 ℃ or 20-30 ℃, the reaction
time is 3-24 hours (h), such as 3h, 5h, 7h, The range of 10h, 12h, 15h, 18h, 20h, or any two of them, is
preferably 3 to 10 hours. Relatively speaking, if the reaction temperature is lower, the reaction is slower and
the reaction time is longer, and the reaction temperature is too high, which will also increase the generation of
by-products to a certain extent, affect the yield and purity of the target product, and control the bromination
reaction. The temperature is within the above range, which is conducive to taking into account the reaction
efficiency and the yield and purity of the target product. Generally, 20 to 30 ° C is preferred. Within this
temperature range, the target product has high purity and few by-products, and the reaction rate is relatively
fast at the same time. The reaction time It is short, and the reaction temperature is milder and easy to control,
and the specific operation can be carried out at room temperature.
During specific implementation, 2-chlorobenzonitrile can be mixed with a solvent to obtain a first mixed
system; after the first mixed system is cooled to 0±5°C, a brominated reagent (preferably added in batches) is
added to the first mixed system, and then controlled The temperature of the system is the first reaction
temperature (such as 20 to 30° C.), and the bromination reaction is carried out under stirring; wherein, the
bromination reaction can be tracked by high performance liquid chromatography (HPLC), that is, the 2 in the
reaction system can be detected by HPLC. -Chlorobenzonitrile, when the ratio of the peak area of 2-
chlorobenzonitrile in the reaction system to the sum of the peak areas of 2-chlorobenzonitrile and the
bromination reaction product converted from 2-chlorobenzonitrile in the system is less than 1.0% , that is, stop
stirring, the bromination reaction ends, and the first product system containing 5-bromo-2-chlorobenzonitrile

is obtained, and the first product system is filtered, washed with water, and concentrated under reduced
pressure successively to obtain 5-bromo-2- The chlorobenzonitrile product (generally a yellow solid with a
HPLC purity of more than 96%) can be subjected to subsequent hydrolysis and other processes without further
purification.
Under normal circumstances, the hydrolysis reaction is carried out in water. In the specific
implementation, the hydrolysis reaction can be carried out after mixing 5-bromo-2-chlorobenzonitrile, alkali,
and water. The mixed system is alkaline, and the system can be detected by a wide range of pH test paper or
pH meter to ensure that the system is alkaline.
In some embodiments, in the above step (2), the molar ratio of 5-bromo-2-chlorobenzonitrile to the base
is 1:(1.0-5.0), such as 1:1, 1:2, 1:3, 1 : 3.5, 1:4, 1:5 or the range of any two of them, preferably 1: (1～3.5),
which is beneficial to the more thorough and complete hydrolysis of 5-bromo-2-chlorobenzonitrile, and avoids
the introduction of subsequent The process thus produces impurities in the final product (5-bromo-2-
chlorobenzoic acid). During specific implementation, the molar amount of 5-bromo-2-chlorobenzonitrile can
be converted according to the HPLC purity and quality of the 5-bromo-2-chlorobenzonitrile product.
The above-mentioned alkali can specifically include an inorganic alkali, and the inorganic alkali can
include at least one of sodium hydroxide, potassium hydroxide, potassium dihydrogen phosphate, potassium
carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium
phosphate, and potassium hydrogen phosphate. kind.
Relatively speaking, if the hydrolysis reaction temperature is too low, the hydrolyzed products are mostly
intermediates, and the hydrolysis is incomplete, and if the hydrolysis temperature is too high, the chlorine and
bromine on the 5-bromo-2-chlorobenzonitrile are easily replaced by hydroxyl groups and hydrolyzed. , to
generate by-products, considering these factors comprehensively, in some preferred embodiments, the general
conditions for controlling the hydrolysis reaction are: the reaction temperature (referred to as the second
reaction temperature) is 30 ℃ ~ 150 ℃, such as 30 ℃, 50 ℃, 60 ℃ °C, 80 °C, 90 °C, 100 °C, 120 °C, 150
°C, or the range of any two of them, preferably 60 to 100 °C, and the reaction time is 2 to 24 hours, such as 2h,
5h, 8h, 10h, 12h , 15h, 18h, 20h or the range of any two of them, preferably 4 to 8 hours.
In some embodiments, step (2) may include: after the hydrolysis reaction is completed, adding a protonic
acid to the system to make the system acidic, so as to achieve a contact reaction between 5-bromo-2-
chlorobenzoate and the protonic acid, the In the process, after the hydrolysis reaction finishes, it is not
necessary to purify the 5-bromo-2-chlorobenzoic acid, and directly adding a protonic acid to it to adjust the
system to be acidic, so that the 5-bromo-2-chlorobenzoate and the The protonic acid contact reaction can
prepare 5-bromo-2-chlorobenzoic acid product in high yield and purity, and the operation is simpler.
In general, in step (2), the amount of protonic acid added can be controlled as follows: the molar ratio of
5-bromo-2-chloroformate to protonic acid is 1:(2.0～10.0), for example 1:2,1 : 5, 1:7, 1:10 or the range of any
two of them, this condition can ensure that the 5-bromo-2-chlorobenzoate is more completely free, increasing
the 5-bromo-2-chlorobenzene yield of formic acid.
As mentioned above, after the hydrolysis reaction finishes, 5-bromo-2-chlorobenzoic acid can not be
purified, and directly add protic acid therein to adjust the system to be acidic, so that 5-bromo-2-
chlorobenzoate and 5-bromo-2-chlorobenzoic acid are Protic acid contact reaction, in this case, the mole
number of 5-bromo-2-chloroformate can be converted according to the consumption of 5-bromo-2-
chlorobenzonitrile, that is, during specific operation, 5-bromo-2-chloroformate can be controlled The molar
ratio of -2-chlorobenzonitrile to protonic acid is 1:(2.0～10.0), such as 1:2, 1:3, 1:5, 1:7, 1:10, etc., preferably
1:(2～3 ), the molar weight of protonic acid should not be less than the summation of the molar weight of 5-
bromo-2-chlorobenzonitrile and the molar weight of alkali, so that the system is acidic, and the system can be
detected by extensive pH test paper or pH meter during specific implementation, to ensure that the system is
acidic.
Specifically, the protic acid may include an inorganic acid, for example, including at least one of sulfuric
acid, hydrochloric acid, nitric acid, hydrobromic acid, and phosphoric acid. Under normal circumstances, these
inorganic acids contain water. In the specific implementation, inorganic acids with higher concentrations can
be used, such as concentrated hydrochloric acid. The molar ratio of -2-chlorobenzonitrile to the solute
(excluding water) in the mineral acid containing water, for example, when the mineral acid is concentrated
hydrochloric acid, it refers to 5-bromo-2-chlorobenzonitrile and the HCl ( The molar ratio of excluding water)
can be converted into the amount of concentrated hydrochloric acid according to the concentration of
concentrated hydrochloric acid and the required molar amount of HCl.
After further research, the conditions for the contact reaction between 5-bromo-2-chlorobenzoate and
protic acid can be: the reaction temperature (referred to as the third reaction temperature) is -10°C to 100°C,
such as -10°C, 0°C , 10°C, 30°C, 50°C, 80°C, 100°C or any two of them, preferably -10°C to 50°C, and the
reaction time is 2 to 12 hours, such as 2h, 3h, 5h, 8h, The range of 10h, 12h or any two of them is preferably 2

to 3h.
In the above-mentioned preparation process, the contact reaction of 5-bromo-2-chlorobenzoate and
protonic acid can be carried out in a solution system formed by water, and the carboxylate is easily soluble in
water to make 5-bromo- 2-Chlorobenzoate is freed in an acidic medium to obtain 5-bromo-2-chlorobenzoic
acid in high yield and purity. During specific implementation, 5-bromo-2-chlorobenzonitrile, alkali, and water
can be mixed to obtain a second mixed system; the second mixed system can be adjusted to the second
reaction temperature (eg, 90° C.), and hydrolyzed under stirring. Reaction, in this stirring process, the system
is gradually clarified, and 5-bromo-2-chlorobenzonitrile is detected by HPLC, and the peak area of 5-bromo-2-
chlorobenzonitrile in the reaction system and the 5-bromo-2-chlorobenzonitrile in the system after the
hydrolysis reaction are treated. -When the ratio of the sum of the peak areas of the hydrolysis reaction product
converted into chlorobenzonitrile and 5-bromo-2-chlorobenzonitrile is less than 1.0%, the stirring is stopped,
and the hydrolysis reaction is terminated to obtain a mixture containing 5-bromo-2-chlorobenzonitrile The
second product system of benzoate; the second product system is cooled to the third reaction temperature,
protonic acid is added therein (for example, the protonic acid is added dropwise to the second product system),
and the reaction is carried out under stirring to generate 5-Bromo-2-chlorobenzoic acid obtains the third
product system containing 5-bromo-2-chlorobenzoic acid; then the third product is subjected to suction
filtration, and after rinsing the obtained filter cake with ice water, The filter cake was dried at 40±5°C for 10-
14 hours to obtain 5-bromo-2-chlorobenzoic acid product (usually a white solid).
In order to make the objectives, technical solutions and advantages of the present invention clearer, the
technical solutions of the present invention will be clearly and completely described below with reference to
specific embodiments. Obviously, the described embodiments are part of the embodiments of the present
invention, not all of them. Example. 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. Unless otherwise specified, the reagents used below are all
conventional reagents, which can be purchased commercially or prepared according to conventional
preparation methods.
In the following examples, the reaction formula of synthesizing 5-bromo-2-chlorobenzoic acid is shown
as follows:

Example 1
Add 350ml of dichloromethane, 68.8g (0.5mol, 1.0eq) of 2-chlorobenzonitrile to a 500ml four-necked
flask with mechanical stirring, a thermometer and a condenser, cool down to 0±5°C in an ice-water bath, and
then divide into it. 89g (0.5mol, 1.0eq) of N-bromosuccinimide was added in batches, the temperature of the
system was adjusted to 20-30°C, and the reaction was stirred for 5 hours to obtain the first product system.
Detected by HPLC, in the first product system, The ratio of the peak area of 2-chlorobenzonitrile to the sum of
the peak areas of each substance in the first product system is <1.0%, the peak area of 3-bromo-2-
chlorobenzonitrile and the peak area of each substance in the first product system The ratio of the sum of
<3.0%, the ratio of the peak area of 5-bromo-2-chlorobenzonitrile to the sum of the peak areas of each
substance in the first product system is ≥96%, wherein the sum of the peak areas of each substance is
substantially equal to The sum of the peak area of 2-chlorobenzonitrile, the peak area of 3-bromo-2-
chlorobenzonitrile, and the peak area of 5-bromo-2-chlorobenzonitrile;
The first product system was filtered, washed with water, and concentrated to dryness under reduced
pressure to obtain 5-bromo-2-chlorobenzonitrile product (yellow solid, about 97.65 g) with a purity of 97%
detected by HPLC (that is, 5-bromo-2-chlorobenzonitrile was detected by HPLC at 97%). The 2-
chlorobenzonitrile product is detected, wherein the ratio of the peak area of 5-bromo-2-chlorobenzonitrile to
the total peak area obtained by HPLC detection (sum of the peak areas of each substance in the product) is
about 97%);
All the above-obtained 5-bromo-2-chlorobenzonitrile products were added to the mixed solution
containing 500 ml of water and 36 g (0.899 mol, 1.8 eq) of sodium hydroxide, and the temperature was slowly
raised to 90 ° C through a hot water bath, and kept stirring for 4 hours. (HPLC detected 3-bromo-2-
chlorobenzonitrile<1.0%) to obtain the second product system; then the hot water bath was removed, and the
system was slowly cooled to 5±5°C through an ice-water bath, and then 140.7g concentrated solution was
added dropwise to it. Hydrochloric acid (about 1.35mol of HCl, 2.7eq)), along with the dropwise addition of
concentrated hydrochloric acid, a large amount of white solids were formed in the system, after the dropwise
addition was completed, the third product system was obtained by thermally stirring for 3 hours; the third
product system was pumped Filter, use 100ml ice water to rinse the obtained filter cake, then dry it, then place 
it in a circulating oven to dry at 40 ° C for 12 hours to obtain 5-bromo-2-chlorobenzoic acid product (white
solid, about 97.50g) ;
The 5-bromo-2-chlorobenzoic acid product was detected by 1 HNMR, 13 CNMR and LC-MS, and the
results were as follows: 1 H NMR (400MHz, CDCl 3
)δ10.05(b, 1H), 8.13(s, 1H), 7.58(d, J=8.0Hz, 1H),
7.35(d, J=8.0Hz, 1H); 13 C NMR (400MHz, CDCl ) 3
)d 165.93, 132.99, 132.86, 132.41, 130.55, 130.39,
125.02; MS-ESI: m/z, 233 (MH). Among them, the 1 HNMR of the 5-bromo-2-chlorobenzoic acid product is
shown in Figures 1 and 2, and Figure 2 is an enlarged view showing the 1 HNMR result of the product more
clearly (the peak near 10.05 is 5-bromo-2-chlorobenzene The peak of the active hydrogen of the carboxyl
group of formic acid generally has a large drift or even no peak phenomenon), and the mass spectrum is shown
in Figure 3. It can be known from the detection results of HNMR, 13 CNMR and LC-MS that the white solid
obtained in this example is 5-bromo-2-chlorobenzoic acid.
According to the following process, the yield of 5-bromo-2-chlorobenzoic acid product was 82.8%, and
the HPLC purity was 99.0% (the calculation methods of yield and HPLC purity in Examples 2 and 3 are the
same as in this example):
(1) Yield w=x1/x2, x1 is the mass (about 97.5 grams) of the 5-bromo-2-chlorobenzoic acid product
obtained through the above preparation process divided by the molecular weight of 5-bromo-2-chlorobenzoic
acid The actual mole number calculated, x2 is the theoretical mole number of the 5-bromo-2-chlorobenzoic
acid converted according to the consumption (mol number) of 2-chlorobenzonitrile;
(2) HPLC purity is calculated according to the following process: 5-bromo-2-chlorobenzoic acid product
is carried out HPLC detection, obtains the peak area of each material wherein, calculates the sum of the peak
area of each material to be A total
, wherein the peak area of 5-bromo-2-chlorobenzoic acid is A 1
, then HPLC
purity=A 1
/A total
.
Example 2
Add 688ml of dichloromethane, 137.6g (1.0mol, 1.0eq) of 2-chlorobenzonitrile to a 1000ml four-necked
flask with mechanical stirring, a thermometer and a condenser, cool down to 0±5°C in an ice-water bath, and
then divide into it. 145.86g (0.51mol, 0.51eq) of dibromohydantoin were added in batches, the temperature
was controlled at 20-30°C, and the reaction was stirred for 5 hours to obtain the first product system, which
was detected by HPLC. In the first product system, the content of 2-chlorobenzonitrile was The ratio of the
peak area to the sum of the peak areas of each substance in the first product system is <0.5%, and the ratio of
the peak area of 3-bromo-2-chlorobenzonitrile to the sum of the peak areas of each substance in the first
product system is <1.0 %, the ratio of the peak area of 5-bromo-2-chlorobenzonitrile to the sum of the peak
areas of each substance in the first product system is ≥98%, wherein the sum of the peak areas of each
substance is substantially equal to that of 2-chlorobenzonitrile. Sum of peak area, peak area of 3-bromo-2-
chlorobenzonitrile, and peak area of 5-bromo-2-chlorobenzonitrile;
The first product system was successively filtered, washed with water, and concentrated to dryness under
reduced pressure to obtain 5-bromo-2-chlorobenzonitrile product (yellow solid, about 199.6 g) with a purity of
98% detected by HPLC (that is, 5-bromo-2-chlorobenzonitrile was detected by HPLC at 98%). The 2-
chlorobenzonitrile product is detected, wherein the ratio of the peak area of 5-bromo-2-chlorobenzonitrile to
the total peak area obtained by HPLC detection (sum of the peak areas of each substance in the product) is
about 98%);
All the above-obtained 5-bromo-2-chlorobenzonitrile products were added to the mixed solution
containing 1000ml of water and 72g (1.8mol, 1.8eq) of sodium hydroxide, slowly heated to 90°C through a
hot water bath, and kept stirring for 4 hours (HPLC detected 3-bromo-2-chlorobenzonitrile<1.0%) to obtain
the second product system; then the hot water bath was removed, and the system was slowly cooled to 5±5°C
by an ice-water bath, and then 281.6 g concentrated solution was added dropwise to it. Hydrochloric acid
(about 2.7mol, 2.7eq of HCl), the system has a large amount of white solids to form, after the dropwise
addition is completed, heat preservation and stirring for 3 hours to obtain the third product system; The filter
cake was rinsed, then dried by suction, and then placed in a circulating oven for drying at 40° C. for 12 hours
to obtain 5-bromo-2-chlorobenzoic acid product (white solid, about 200 g) with a yield of 85.9% and HPLC
purity is 99.90%.
results were consistent with Example 1, which proved that the obtained white solid was 5-bromo-2-
chlorobenzoic acid.
Example 3
To the 1000ml four-necked flask with mechanical stirring, thermometer and condenser, add 500ml of
dichloromethane, 137.6g (1.0mol) 2-chlorobenzonitrile, cool down by 0±5°C in an ice-water bath, and then
slowly dropwise add 160g to it. (1.0mol) mixed solution of bromine and 160ml of dichloromethane, then

adjust the temperature of the system to 20-30 ° C, and stir the reaction for 5 hours to obtain the first product
system, detected by HPLC, in the first product system, 2 - the ratio of the peak area of chlorobenzonitrile to
the sum of the peak areas of each substance in the first product system is <0.5%, and the ratio of the peak area
of 3-bromo-2-chlorobenzonitrile to the peak area of each substance in the first product system The ratio of
sum <1.0%, the ratio of the peak area of 5-bromo-2-chlorobenzonitrile to the sum of the peak areas of each
substance in the first product system is ≥97%, 3,5-dibromo-2-chlorobenzoic acid The ratio of the peak area to
the sum of the peak areas of each substance in the first product system is less than 1.0%, wherein the sum of
the peak areas of each substance is substantially equal to the peak area of 2-chlorobenzonitrile, 3-bromo-2-
chlorobenzene The sum of the peak area of nitrile, the peak area of 5-bromo-2-chlorobenzonitrile, and the
peak area of 3,5-dibromo-2-chlorobenzoic acid;
The first product system was concentrated to dryness under reduced pressure to obtain 5-bromo-2-
chlorobenzonitrile product (yellow solid, about 200 g), the purity detected by HPLC was 97% (that is, the 5-
bromo-2-chlorobenzonitrile product was subjected to HPLC analysis. Detection, wherein, the ratio of the peak
area of 5-bromo-2-chlorobenzonitrile to the total peak area obtained by HPLC detection (sum of the peak areas
of each substance in the product) is about 97%);
All the above-obtained 5-bromo-2-chlorobenzonitrile products were added to a mixed solution containing
1500ml of water and 112g (2.8mol, 2.8eq) of sodium hydroxide, and the temperature was slowly raised to
90°C through a hot water bath, and kept stirring for 6 hours. (HPLC detected 3-bromo-2-
chlorobenzonitrile<1.0%) to obtain the second product system; then the hot water bath was removed, and the
system was slowly cooled to 5±5°C by an ice-water bath, and then 281.6 g concentrated solution was added
dropwise to it. Hydrochloric acid (HCl is about 2.7mol, 2.7eq), the system has a large amount of white solids
to form, after the dropwise addition is completed, keep stirring for 3 hours to obtain the third product system;
The third product system is suction filtered, and 200ml ice water is used to The filter cake was rinsed, then
drained, and then placed in a circulating oven for drying at 40 ° C for 12 hours to obtain 5-bromo-2-
chlorobenzoic acid product (white solid, about 205 g), the yield W was 87.4%, HPLC The purity is 99.2%.
results were consistent with Example 1, which proved that the obtained white solid was 5-bromo-2-
chlorobenzoic acid.
The embodiments of the present invention have been described above. However, the present invention is
not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc.
made within the spirit and principle of the present invention shall be included within the protection scope of
the present invention.


CN113321577 Preparation Method of 5-Bromo-2-Chlorobenzoic Acid

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3/23/22, 2:55 PM CN113321577 Preparation method of 5-bromo-2-chlorobenzoic acid

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The preparation method of 5-bromo-2-chlorobenzoic

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