CN113773194 2021 5-Bromo-2-Chloro-Benzoic Acid As Raw Material For Hypoglycemic Drug Synthesis

3/23/22, 11:58 AM CN113773194 Preparation method of 5-bromo-2-chloro-benzoic acid as raw material for hypoglycemic drug synthesis
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1. CN113773194 - THE PREPARATION METHOD OF 5-

BROMO-2-CHLORO-BENZOIC ACID AS THE
SYNTHETIC RAW MATERIAL OF HYPOGLYCEMIC
DRUG
National Biblio.Data Description Claims Documents
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[EN ]
Preparation method of 5-bromo-2-chloro-benzoic

acid as raw material for hypoglycemic drug synthesis
technical field
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a
preparation method and application of 5-bromo-2-chloro-benzoic acid as a synthetic raw material for
hypoglycemic drugs.
Background technique
The compound of formula I, 5-bromo-2-chloro-benzoic acid, is an important raw material for the
preparation of antidiabetic drugs Dapagliflozin and Empagliflozin.

The reported preparation methods of the compound of formula I mainly include the following.
Method 1: Chinese patent CN105622382B reports that 2-chloro-trichloromethyl-benzene is brominated
and then hydrolyzed to prepare the compound of formula I. However, the cost of the reaction raw material 2-
chloro-trichloromethyl-benzene is relatively high, and it is difficult to complete the hydrolysis, and the
reaction will produce more isomer impurities, which need to be further removed by recrystallization, thereby
affecting the yield and product purity.

Method 2: Chinese patents CN107954852A, CN110105193A and CN110590541A all reported using 2-
chlorobenzoic acid as a raw material, using for example sodium bromide and sodium periodate, bromine, N-
bromosuccinimide, dibromohydantoin, etc. Different bromination reagents are brominated, but due to the
nature of the reaction, about 10% of isomer impurities will be generated during the bromination reaction, the
product yield and purity of the compound of formula I will be affected, and more waste will be generated.
Acid, not suitable for industrial production.

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN345638844&_cid=P21-L1368T-27741-1 1/12

Although Chinese patent CN110002989B has reported that 2-chlorobenzoic acid is a raw material and
NBS/sulfuric acid is a reaction system, adding inhibitor sodium sulfide, potassium sulfide or sodium sulfite,
the compound of formula I can be efficiently prepared, inhibiting 4-bromo-2-chlorobenzene Formation of
formic acid impurities. However, whether the inhibitor exists in the strong acid system, and whether it will
produce 4-bromo-2-chlorobenzoic acid impurities, remains to be discussed.
Method 3: Chinese patent CN108250060A reports a method for preparing the compound of formula I
with salicylic acid as a raw material. Although this method can effectively reduce the generation of isomers,
the chlorination step uses a higher reaction temperature of 120-180 ° C, which requires higher equipment, and
uses unenvironmental chlorination reagents carbon tetrachloride, boron trichloride, Phosphorus trichloride,
etc., so this method is not ideal.

Method 4: Chinese patent CN111925289A reported that 2-chlorobenzoic acid was used as a raw material,
and the compound of formula I was prepared through chlorination, amidation, cyclization, bromination and
hydrolysis successively. This route has relatively long reaction steps, uses a highly corrosive acid chloride
reagent in the chlorination reaction, and uses a dangerous butyllithium reagent in the bromination reaction,
which has high cost and long production cycle, and is not suitable for industrial production.

Method 5: Chinese patent CN112979448A reported a method for preparing the compound of formula I by
using 2-chlorobenzoic acid as a raw material and using dibromoamino silica gel as a brominating reagent. In
this method, the raw material cost of amino silica gel is relatively high. In the method for preparing dibromo
amino silica gel, bromine and potassium carbonate of more than 2 times equivalent are used as acid binding
agents. Although amino silica gel can be recycled and applied mechanically, it is finally treated as solid waste.
Moreover, the bromination reaction uses 1-chlorobutane and 1-bromobutane as the reaction solvent, and iron
trifluoromethanesulfonate as the catalyst, and the reaction is carried out at 60-70° C., resulting in higher cost.

In summary, the reported preparation method of the compound of formula I has problems such as long
reaction steps, insufficient environmental protection, many isomer impurities, and high cost, which brings
certain difficulties to industrial scale production. Therefore, it is necessary to further study simple and efficient
synthetic methods suitable for the industrial production of compounds of formula I.
SUMMARY OF THE INVENTION
In order to overcome the shortcomings and deficiencies existing in the prior art, the present invention
provides a new method for synthesizing the compound 5-bromo-2-chlorobenzoic acid of formula I. The
method has the characteristics of convenient operation, cheap and easy-to-obtain raw and auxiliary materials,
high product yield, good purity of intermediates and target products, etc., and is easy to carry out industrial
production.
In a first aspect, the present invention provides a method for preparing a compound of formula I, the
method comprising:
Step (1): The compound of formula II is prepared by diazochlorination of the compound of formula III,
and
Step (2): the compound of formula II is hydrolyzed to obtain the compound of formula I,


in:
R is selected from: C 1-6
Alkyl, C 2-6
Alkenyl, C 2-6
Alkynyl, C 3-8
Cycloalkyl, C 3-8
Cycloalkyl-C 1-6
Alkyl,
C 6-10
Aryl, C 6-10
Aryl-C 1-6
Alkyl, 5-10-membered heteroaryl, 3-12-membered heterocycloalkyl, 5-10-
membered heteroaryl-C 1-6
Alkyl, 3-12 membered heterocycloalkyl-C 1-6
Alkyl, C 1-6
Alkoxycarbonyl, C 1-6
Alkoxycarbonyl C 1-6
Alkyl, C 6-10
Aryl-C 1-6
Alkoxycarbonyl, C 6-10
Aryl-C 1-6
Alkoxycarbonyl C 1-6
alkyl
groups, each of which is optionally substituted with one or more groups independently selected from halogen,
amino, -NH(C 1-6
Alkyl), -N(C 1-6
alkyl) 2
, hydroxyl, C 1-6
Alkyl, C 1-6
Alkoxy, halogen substituted C 1-6
Alkyl,
halogen substituted C 1-6
Alkoxy, C 3-8
Cycloalkyl, C 6-10
Aryl, 5-10 membered heteroaryl or 3-12 membered
heterocycloalkyl;
Alternatively, when R is H, step (1) as described above is carried out to obtain the compound of formula I
directly.
In a preferred embodiment, R is selected from: C 1-6
Alkyl, C 2-6
Alkenyl, C 3-8
Cycloalkyl, C 3-8
Cycloalkyl-C 1-6
Alkyl, C 6-10
Aryl or C 6-10
Aryl-C 1-6
alkyl groups, each of which is optionally substituted
with one or more groups independently selected from halogen, amino, -NH(C 1-6
Alkyl), -N(C 1-6
alkyl) 2
,
hydroxyl, C 1-6
Alkyl, C 1-6
Alkoxy, halogen substituted C 1-6
Alkyl or halogen substituted C 1-6
alkoxy.
In another preferred embodiment, R is selected from the group consisting of: methyl, ethyl, propyl,
isopropyl, allyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, n-hexyl, cyclohexyl, phenyl or
benzyl.
In step (1), the preparation of the compound of the formula III by the diazonium chlorination reaction to
the compound of the formula II refers to: the compound of the formula III is first subjected to a diazotization
reaction, and then the compound of the formula II is prepared by a two-step chlorination reaction; or the
compound of the formula Compound III is prepared by a one-pot method of diazonium chlorination to prepare
compound of formula II.
In the two-step reaction, the diazotization reaction means that the compound of formula III is in an acidic
system, and the temperature is controlled to be lower than 20°C, for example, -10 to 15°C, and a diazotization
reagent is added for the reaction.
Described diazotization reagent can be selected from nitrous acid or its salt or C 1-6
Alkyl esters such as
nitrous acid, sodium nitrite, potassium nitrite, methyl nitrite, ethyl nitrite, isoamyl nitrite or tert-butyl nitrite.
The chlorination reaction is a reaction in which the diazotized group is chlorinated in a solution
containing chloride ions in the presence of a copper catalyst. For example, the chlorination reaction may be
performed by chlorination of the above-mentioned diazotized group in a solution containing chloride ions at
-10 to 40°C. The chloride ion-containing solution may be selected from hydrochloric acid, sodium chloride,
potassium chloride, cupric chloride, ferric chloride or ferrous chloride solutions.
The copper catalyst is selected from metallic copper, cuprous chloride, cupric chloride, cuprous bromide
or cuprous iodide.
In a particularly preferred embodiment, step (1) comprises: adding the compound of formula III to an
acidic solvent, controlling the reaction temperature to be -10 to 15° C., dropping a diazotization reagent to
obtain a diazotization reaction solution. Then, the temperature is controlled to be -10 to 40° C., the
diazotization reaction solution is added dropwise to a solution containing a chloride ion containing a copper
catalyst, the compound of formula II is precipitated, filtered, and washed with water to obtain the compound of
formula II. The product does not need to be dried, and the next step reaction is carried out directly.
In another preferred embodiment, in step (1), the compound of formula III is prepared by a one-pot
method to prepare the compound of formula II, which comprises: adding the compound of formula III to an
acidic reaction solution containing a copper catalyst and chloride ions , stir evenly, control the reaction
temperature from -10 to 70 DEG C, drop the diazotization reagent to carry out the reaction, and obtain the
compound of formula II. The product was filtered, washed with water, and then directly proceeded to the next
step.
In the case where the copper catalyst is metal copper element, after the product is filtered, the compound
of formula II is prepared by using a solvent selected from toluene, hexane, n-heptane, methanol, ethanol or
isopropanol or its mixed solution with water. Dissolve and filter to obtain metal copper catalyst, which is
recycled and used. Then, the solution of the compound of formula II is distilled to dryness, and the next step
reaction is directly carried out, or crystallization is separated out, and the next step reaction is directly carried

out after centrifugation.
In step (2), the compound of formula II is hydrolyzed in an aqueous alkali metal hydroxide solution to
obtain the compound of formula I.
In a preferred embodiment, the compound of formula II is hydrolyzed in an aqueous alkali metal
hydroxide solution, and water-insoluble impurities are removed by extraction with an organic solvent,
followed by acidification, centrifugation, and drying to obtain the compound of formula I.
The alkali metal hydroxide aqueous solution can be selected from lithium hydroxide, sodium hydroxide
or potassium hydroxide aqueous solution, or a mixture thereof. The organic solvent used to remove impurities
can be selected from non-polar or polar aprotic organic solvents such as hexane, n-heptane, isopropyl acetate,
toluene, xylene or chlorobenzene, or a combination of two or more thereof. mixture.
The acid used in the acidification is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, phosphoric acid, nitric acid, formic acid or acetic acid, or a mixture of two or more thereof.
In a second aspect, the present invention provides a method for preparing a compound of formula III,

The method includes:
Step (a): Reaction of a compound of formula IV with a brominating reagent to give a compound of
formula III, wherein R is as defined above in the first aspect.
In a preferred embodiment, the method comprises: dissolving the compound of formula IV in a polar
solvent, controlling the reaction temperature to be, for example, 5-50° C., dropwise adding a brominating
reagent or a solution thereof to react to obtain the compound of formula III. After the reaction is completed,
the reaction solution is added to tap water to precipitate the compound of formula III, which can be directly
used for the preparation of the compound of formula II after centrifugation.
The polar solvent is selected from: acetonitrile, tetrahydrofuran, methyltetrahydrofuran, N,N-
dimethylformamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, formic acid , acetic
acid or water, or a mixture of two or more thereof.
Described bromination reagent is selected from: bromine, hydrobromic acid, lithium bromide, sodium
bromide, potassium bromide, sodium bromate, dibromohydantoin, N-bromoacetamide, N-bromosuccinimide ,
phenyltrimethylammonium tribromide, (bromomethyl)triphenylphosphonium bromide, or a mixture of two or
more thereof.
In a third aspect, the present invention provides a method for preparing a compound of formula I, the
method comprising steps (a), (1) and (2) as described above:

wherein R is as defined above.
The reaction conditions and preferred embodiments of steps (a), (1) and (2) are as defined above.
In a fourth aspect, the present invention provides a method for preparing a compound of formula VI,
comprising the following steps:

Step (3): compound of formula I is reacted with compound of formula VII by Friedel-Crafts acylation to
prepare compound of formula V,

where R 1
Selected from: H, C 1-6
an alkyl group such as methyl or ethyl, 3-tetrahydrofuranyl, 3-S-
tetrahydrofuranyl or 3-R-tetrahydrofuranyl; and
Step (4): The compound of formula V is reduced to obtain the compound of formula VI.
In a preferred embodiment, the present invention provides a method for preparing a compound of formula
VI comprising steps (1), (2), (3) and (4):


where R 1
Selected from: H, C 1-6
alkyl, such as methyl or ethyl, 3-tetrahydrofuranyl, 3-S-
tetrahydrofuranyl or 3-R-tetrahydrofuranyl, and R is as defined in the first aspect,
wherein steps (1), (2), (3) and (4) are as defined above.
In a preferred embodiment, the method comprises: (1) subjecting the compound of formula III to
diazonium chlorination to prepare the compound of formula II, (2) hydrolyzing the compound of formula II to
obtain the compound of formula I, (3) passing the compound of formula I through Friedel-Crafts acylation
reaction with compound of formula VII to give compound of formula V, and (4) reduction of compound of
formula V to give compound of formula VI.
The reaction conditions and preferred embodiments of steps (1) and (2) are as defined above.
In this method, preferably, step (3) comprises: the compound of formula I obtains an acid chloride in a
weakly polar solvent under the action of an acylating agent, and then reacts with the compound of formula VII
in a weakly polar solvent under the action of a Lewis acid A compound of formula V is obtained.
In a more preferred embodiment, step (3) comprises: under the action of an acylating agent, the
compound of formula I obtains an acid chloride in a weakly polar solvent, and then under the action of a
Lewis acid, reacts with formula VII in a weakly polar solvent The compound is reacted, and the reaction
temperature is controlled at -10 to 20° C. until the reaction is completed, and the reactant is concentrated and
crystallized to obtain the compound of formula V. The specific post-processing of the reactant may include:
adding water to quench, washing the organic phase with water, concentrating, crystallization, centrifuging, and
drying to obtain the compound of formula V.
The acylating reagent is selected from oxalyl chloride, thionyl chloride, phosphorus trichloride,
phosphorus pentachloride or phosphorus oxychloride.
The Lewis acid is selected from aluminum chloride, ferric chloride, cupric chloride or aluminum
bromide.
The less polar solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane,
trichloromethane, isopropyl ether or methyl tert-butyl ether, or a mixture of two or more thereof.
The solvent used for crystallization is selected from toluene, hexane, n-heptane, methanol, ethanol,
isopropanol, dichloromethane, isopropyl ether, methyl tert-butyl ether or water, or a mixture of two or more
thereof .
In the method, step (4) comprises: dissolving the compound of formula V in an organic solvent, and
reducing the compound of formula VI under the action of a reducing agent and an auxiliary agent.
In a more preferred embodiment, step (4) comprises: dissolving the compound of formula V in an organic
solvent, under the action of a reducing agent and auxiliary, controlling the temperature at -10 to 80° C.,
reducing, and crystallizing to obtain the formula VI compound.
The organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, isopropyl ether, methyl
tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, pentane, hexane,
cyclohexane, n- Heptane or water, or a mixture of two or more thereof.
The reducing agent is selected from lithium borohydride, sodium borohydride, potassium borohydride,
borane, triethylsilane, trimethylsilane, tetramethyldisiloxane or lithium aluminum hydride.
The auxiliary agent is selected from aluminum chloride, ferric chloride, cupric chloride, aluminum
bromide, trifluoroacetic acid, trifluoromethanesulfonic acid or boron trifluoride ether.
The solvent used for crystallization is selected from methanol, ethanol, isopropanol, acetonitrile,
isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene,
pentane, hexane, cyclohexane, n-heptane or water, or a mixture of two or more of them.
In another preferred embodiment, the present invention provides a process for the preparation of a
compound of formula VI comprising steps (a), (1), (2), (3) and (4):

wherein steps (a), (1), (2), (3) and (4) and preferred embodiments are as defined above, R and R 1
as
defined above.
In a fifth aspect, the present invention provides the use of the compound of formula III in the preparation
of hypoglycemic drugs dapagliflozin or empagliflozin. 
Specifically, the present invention provides a method for preparing dapagliflozin or empagliflozin, the
method comprising any one or more steps as described in the first, second, third and fourth aspects above, that
is, the method includes any one or more of steps (a), (1), (2), (3) and (4) above, wherein R and R 1
as defined
above.
For example, the present invention provides a method of preparing dapagliflozin, the method comprising
the step of preparing a compound of formula VI from a compound of formula III,

wherein steps (1), (2), (3) and (4) are as defined above, R and R 1
as defined above.
Using the compound of formula VI as a raw material, dapagliflozin and empagliflozin can be prepared by
referring to the methods of patent applications WO03099836A1 and WO2005092877A1, respectively. Patent
applications WO03099836A1 and WO2005092877A1 are incorporated herein by reference in their entirety.
In a specific embodiment, the present invention provides a method for preparing dapagliflozin, the
method comprising the steps of:

wherein steps (1), (2), (3) and (4) are as defined above, R is as defined above, and R 1
is ethyl and steps
(5), (6), (7) and (8) are as described in the Examples of WO03099836A1.
Compared with the prior art, the present invention has the following advantages:
1. the compound of formula I prepared by the present invention has high yield, good purity and few
isomer impurities;
2. The method for preparing the compound of formula I of the present invention has few steps, the
technique is simple, and the solvent, catalyst and acid used can be recovered and reused, thereby significantly
reducing cost and being suitable for industrialized production;
3. The compound of formula VI, the key intermediate of the hypoglycemic drug further prepared by using
the compound of formula I of the present invention, has a high yield and a purity of 99.9%, thereby providing
reliable quality assurance for the preparation of the final drug.
definition:
For the purpose of interpreting this specification, the following definitions will be used and where
appropriate, terms used in the singular may also include the plural, and vice versa. It is to be understood that
the terminology used herein is for the purpose of describing particular embodiments only and is not intended
to be limiting.
The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "halogen-
substituted" group is intended to include mono- or polyhalogenated groups in which one or more of the same
or different halogens replace one or more hydrogens in the group.
The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group
consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1 to 10, eg, 1 to 6, 1 to 5, 1
to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C 1
-C 6
"Alkyl" refers to a straight
or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which are methyl,
ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl) butyl, isobutyl, sec-butyl or tert-
butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, and the like.
The term "alkenyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon group
consisting of carbon atoms and hydrogen atoms containing at least one double bond. Specifically, an alkenyl
group has 2 to 8, eg, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C 2
-C
6
"Alkenyl" refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl,
propenyl, allyl, butenyl, pentenyl, and the like.
The term "alkynyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon group
consisting of carbon atoms and hydrogen atoms containing at least one triple bond. Specifically, an alkynyl 
group has 2-8, eg, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C 2
-C 6
"Alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl,
propynyl, propargyl, butynyl, and the like.
The term "alkoxy," as used herein, means the group -O-alkyl, wherein alkyl has the meaning set forth
herein. Specifically, the term includes the group -OC 1-6
Alkyl, more specifically -OC 1-3
alkyl. Representative
examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy,
isopropoxy), butoxy (including n-butoxy, isobutoxy, tert-butoxy), pentyloxy (including n-pentyloxy,
isopentyloxy, neopentyloxy), hexyloxy (including n-hexyloxy, isohexyloxy) and the like.
As used herein, the term "halogen substituted C 1
-C 6
"Alkyl" refers to the above-mentioned C 1
-C 6
Alkyl in which one or more (eg 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood
by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same
or different, and may be located on the same or different C atoms. "halogen substituted C 1
-C 6
Examples of
"alkyl" include, for example, -CH 2
F, -CHF 2
, -CF 3
, -CCl 3
, -C 2
F 5
, -C 2
Cl 5
, -CH 2
CF 3
, -CH 2
Cl, -CH 2
CH 2
CF 3
or -CF (CF 3
) 2
Wait.
The term "cycloalkyl" as used herein refers to a monocyclic, fused polycyclic, bridged polycyclic or
spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring
atoms. Cycloalkyl groups can have 3 to 12 carbon atoms (ie C 3
-C 12
cycloalkyl), for example 3 to 10, 3 to 8, 3
to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to,
monocyclic structures, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or
polycyclic (eg, bicyclic) structures, including spiro Ring, fused or bridged systems such as
bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1. 1] Heptyl or
bicyclo[3.2.1] octyl and the like.
The term "cycloalkyl" as used herein also includes "cycloalkenyl". "Cycloalkenyl" means a monocyclic,
fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic unsaturated hydrocarbon ring structure
having the specified number of ring atoms, containing at least one (eg, 1, 2, or 3) carbons carbon double bond.
Cycloalkenyl can have 3 to 12 carbon atoms (ie C 3
-C 12
cycloalkenyl), for example 3 to 10, 3 to 8, 3 to 7, 3 to
6, 5 to 6 carbon atoms. Examples of suitable cycloalkenyl groups include, but are not limited to, monocyclic
structures such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,
cyclohexadienyl, cycloheptene cycloheptadienyl, cycloheptatrienyl, or cyclooctenyl.
The term "heterocycloalkyl" as used herein means a monocyclic, fused, monocyclic, fused ring
comprising one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from O, N and S and the
specified number of ring atoms A polycyclic, spirocyclic or bridged polycyclic non-aromatic saturated ring
structure, or its N-oxide, or its S-oxide or S-dioxide. Heterocycloalkyl may have 3 to 12 ring members (may
be referred to as 3-12 membered heterocycloalkyl), for example 3 to 10 ring members, 3 to 8 ring members, 3
to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 6 ring members. Heterocycloalkyl groups
typically contain up to 4 (eg, 1, 2, 3, or 4) heteroatoms. Examples of suitable heterocycloalkyl groups include,
but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-
pyrrolidinyl). -pyrrolidinyl), tetrahydrofuranyl (eg 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-
tetrahydrofuranyl), tetrahydrothienyl (eg 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl)
thienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl
(such as 4-tetrahydropyranyl), Tetrahydrothiopyranyl (eg 4-tetrahydrothiopyranyl), morpholinyl (eg
morpholino), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepine Cycloheptyl groups such as 1,4-
diazacycloheptyl, 3,6-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl. The atom in the
heterocycloalkyl group to which the rest of the compound is attached can be a carbon atom or a heteroatom, as
long as it is chemically feasible.
The term "heterocycloalkyl" as used herein also includes "heterocycloalkenyl" and refers to a
"heterocycloalkyl" as defined herein containing at least one (eg 1, 2 or 3) double bond, eg pyrroline radicals
(e.g. 1-pyrrolidyl, 2-pyrrolidinyl, 3-pyrrolinyl, 4-pyrrolinyl or 5-pyrrolinyl), dihydrofuranyl (e.g. 1-
dihydrofuranyl, 2-dihydrofuranyl hydrofuranyl, 3-dihydrofuranyl, 4-dihydrofuranyl or 5-dihydrofuranyl),
dihydrothienyl (e.g. 1-dihydrothienyl, 2-dihydrothienyl, 3-dihydrothienyl thienyl or 4-dihydrothienyl),
tetrahydropyridyl (eg 1-, 2-, 3-, 4-, 5- or 6-tetrahydropyridyl), tetrahydropyranyl (eg 4-tetrahydropyridyl)
hydropyranyl) or tetrahydrothiopyranyl (eg 4-tetrahydrothiopyranyl).
The term "aryl" as used herein means a monovalent aromatic hydrocarbon group derived by removing
one hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, the aryl group refers to
a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms.
Specifically, the term includes groups comprising 6 to 14, such as 6 to 10, preferably 6, ring atoms. Particular
aryl groups include phenyl and naphthyl, the most particular aryl group being phenyl.

The term "heteroaryl" as used herein means a monocyclic or fused ring comprising one or more (eg 1, 2,
3 or 4) heteroatoms independently selected from O, N and S and the specified number of ring atoms A
polycyclic aromatic ring structure, or its N-oxide, or its S-oxide or S-dioxide. Specifically, the aromatic ring
structure may have 5 to 10 ring members. Heteroaryl can be, for example, a 5-6 membered monocyclic ring, or
consisting of two 6-membered rings fused, two 5-membered rings fused, a 6-membered ring and a 5-
membered ring fused, or a 5-membered ring fused A fused bicyclic structure formed by a ring and a 4-
membered ring. Heteroaryl rings will typically contain up to 4 heteroatoms, more typically up to 3
heteroatoms, more typically up to 2, such as a single heteroatom independently selected from O, N and S,
where N and S may be in an oxidized state such as N oxide, S=O or S(O) 2
. In one embodiment, the heteroaryl
ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one epoxy atom. For
example, a heteroaryl group can be a fused ring containing 1, 2, 3, or 4 heteroatoms independently selected
from N, O, or S, such as benzofuran, benzothiophene, indole, benzimidazole, indole azole, benzotriazole,
pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine , imidazo[4,5-
b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo [3,4-
c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, purine, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a
]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b]pyrimidine, imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3,2-
b]pyridine oxazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine,
quinoline, isoquinoline , cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-
naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, pyrido[3,2-
d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine , pyrido[2,3-
b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and pyrimidine and
[4,5-d]pyrimidine. For example, a heteroaryl group can be a 5-6 membered heteroaryl group containing 1 or 2
heteroatoms independently selected from N, O, or S. Examples of suitable 5-membered monocyclic heteroaryl
groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl,
oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl; examples of suitable 6-
membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl,
pyrimidinyl, and triazine base. The atom in the heteroaryl group that is attached to the rest of the compound
can be a carbon atom or a heteroatom, as long as it is chemically feasible.
Substituents described as "optionally substituted" mean that the group may be unsubstituted or substituted
by one or more (eg, 0, 1, 2, 3, 4, or 5 or more, or any derivatized therein). range) is substituted with the listed
substituents for that group, wherein the substituents may be the same or different. In one embodiment, an
optionally substituted group is substituted with 1 substituent. In another embodiment, an optionally substituted
group is substituted with 2 substituents. In another embodiment, an optionally substituted group is substituted
with 3 substituents. In another embodiment, an optionally substituted group is substituted with 4 substituents.
As used herein, the term "comprising" or "comprising" means the inclusion of stated elements, integers or
steps, but not the exclusion of any other elements, integers or steps. Herein, when the terms "comprising" or
"comprising" are used, unless otherwise indicated, combinations of the stated elements, integers or steps are
also encompassed.
detailed description
The method of the present invention is further illustrated by the following examples. It should be
understood that the following examples are provided only for a better understanding of the present invention,
and are not intended to limit the scope of the present invention in any way.
Unless otherwise stated, the following various solvents and reagents are commercially available. The
starting materials used are from commercial sources or are further processed by conventional reactions well
known in the art.
Preparation of compounds of formula III
Example 1: Preparation of 5-bromo-2-amino-benzoic acid ethyl ester

41.5kg of 2-aminobenzoic acid ethyl ester was added in 175kg of tetrahydrofuran, stirred to dissolve
clear, controlled reaction kettle temperature 10-35 ℃, dropped into N-bromosuccinimide 44.5kg in batches,
after adding, stirring reaction 30 -60 minutes. 2.5 kg of saturated aqueous sodium bisulfite solution was added,
and then tetrahydrofuran was recovered by distillation under reduced pressure, which could be reused. In the
concentration kettle, add 150kg tap water for pulping, centrifugal, 30kg tap water for washing to obtain 73.2kg
of formula III compound 5-bromo-2-aminobenzoic acid ethyl ester wet product 73.2kg, without drying,
directly used in the next step reaction, the yield is 100% In total, the purity is 99.1%. 
Example 2: Benzyl 5-bromo-2-amino-benzoate

Add 227g of allyl 2-aminobenzoate to 900g of DMF, stir to dissolve, control the temperature of the
reaction kettle to 10-35°C, add 163g of bromine in batches, and after the addition is complete, stir and react for
40-60 minutes. The above-mentioned reaction solution was added to a tap aqueous solution containing 35kg of
sodium sulfite and 350g, and the solid was precipitated, centrifuged, and washed with 50g of tap water to
obtain 346g of 5-bromo-2-amino-benzyl benzoate wet product, without drying, directly proceed to the next
step reaction, The yield is 100%, and the purity is 99.1%.
Example 3: Preparation of 5-bromo-2-amino-benzoic acid allyl ester

Add 176.2g of allyl 2-aminobenzoate to 1000g of DMF, stir to dissolve, control the temperature of the
reactor to 10-35°C, add 205g of dibromohydantoin in batches, and after the addition is completed, stir and
react for 40-60 minutes. The above reaction solution was added to the tap water containing 30g of sodium
sulfite and 300g, the solid was precipitated, centrifuged, and washed with 20g of tap water to obtain 289.3g of
5-bromo-2-amino-allyl benzoate wet product, without drying, proceed directly to the next step Reaction, the
yield is 100%, and the purity is 99.2%.
Preparation of compounds of formula I
Example 4: Preparation of 5-bromo-2-chloro-benzoic acid

method one:
73.2kg of the 5-bromo-2-aminobenzoic acid ethyl ester wet product prepared in Example 1 was added to
300kg of 20% hydrochloric acid solution, then 8.0kg of copper powder was added, and after stirring, the
reaction temperature was controlled at 0-20° C. 40kg of sodium nitrite aqueous solution (containing 17.6kg of
sodium nitrite) was added dropwise, and the stirring was continued for 30 minutes. Then add 80kg of toluene
into the reaction kettle, stir and filter, and recover the copper catalyst, which can be reused. The layers are
separated, and the acidic aqueous phase is reserved for reuse in the next batch. The organic phase was washed
once with 20 kg of tap water, and the organic phase was concentrated to dryness to recover toluene, which
could be reused. Add 80kg of hexane, heat to 50-55°C, stir to dissolve, cool down and crystallize, stir at 0-
10°C for 30 minutes, and centrifuge to obtain 72.5kg of 5-bromo-2-chloro-ethyl benzoate wet product with a
purity of 72.5kg. 99.6%.
72.5kg of the above-mentioned compound of formula II was added to the reactor, then 150kg of tap water
was added, the temperature was controlled at 40-55°C, 38.0kg of 30% NaOH solution was added dropwise,
after stirring and dissolving, 31.0kg of concentrated hydrochloric acid was added dropwise to separate out
solids and centrifuged, After drying at 50-70° C. for 6-8 hours, 53.7 kg of the compound of formula I was
obtained, with a total yield of 91.2% in three steps and a purity of 99.7%.
Method Two:
73.2kg of the 5-bromo-2-aminobenzoic acid ethyl ester wet product prepared in Example 1 was added to
120kg of 20% hydrochloric acid solution, and after stirring, the reaction temperature was controlled from -5 to
6°C, and 40kg of aqueous sodium nitrite was added dropwise. (containing 17.6 kg of sodium nitrite), after the
dropwise addition was completed, stirring was continued for 30 minutes to obtain a 5-bromo-2-aminobenzoic
acid ethyl ester diazide solution, which was set aside for use.
In another reaction kettle, 100kg of concentrated hydrochloric acid and 12.4kg of cuprous chloride were
added, and after stirring and dissolving, the temperature was controlled to 20-30°C, and the above
diazotization solution was added dropwise to precipitate a large amount of solid. After filtration, the filtrate is
reused twice and treated as waste liquid. The filter cake was washed with water and centrifuged to obtain a wet
product of ethyl 5-bromo-2-chlorobenzoate, 71.8 kg, with a purity of 99.5%.
71.8kg above-mentioned 5-bromo-2-chlorobenzoic acid ethyl ester was added in the reactor, then added 
160kg tap water, controlled temperature 40-55 ℃, dripped 38.0kg of 30% NaOH solution, after stirring and
dissolving, dripped 31.0kg Concentrated hydrochloric acid, the solid was precipitated, centrifuged, and dried
at 50-70° C. for 8 h to obtain 52.9 kg of 5-bromo-2-chlorobenzoic acid of formula I, with a total yield of
89.8% in three steps and a purity of 99.6%.
Method three:
346g of 5-bromo-2-amino-benzoic acid benzyl ester wet product prepared in Example 2 was added to
1050g of 20% hydrochloric acid solution, after stirring evenly, the reaction temperature was controlled from -5
to 10°C, and 212g of sodium nitrite aqueous solution was added dropwise. (containing 70.4 g of sodium
nitrite), after the dropwise addition was completed, stirring was continued for 30 minutes to obtain a 5-bromo-
2-aminobenzoic acid ethyl ester diazide solution, which was used for later use.
In another reaction flask, 150 g of concentrated hydrochloric acid and 50 g of cuprous chloride were
added, and after stirring to dissolve, 260 g of toluene was added. The temperature was controlled at 20-40°C,
and the above diazotization solution was added dropwise. After dripping, stir for 60 minutes, separate liquids,
and the aqueous phase is to be treated. The organic phase was washed with 100 g×2 tap water. Then add 1200g
of tap water, heat to 45-55°C, add dropwise 190g of 30% NaOH solution, after stirring to dissolve, add 200g
of concentrated hydrochloric acid dropwise to precipitate a solid, centrifuge, and dry at 50-70°C for 6-9h to
obtain compound 5 of formula I -Bromo-2-chlorobenzoic acid 198g, the total yield of three steps is 87.2%, and
the purity is 99.4%.
According to method 3, 207.7 g of compound 5-bromo-2-chlorobenzoic acid of formula I was prepared
by using the wet product of 5-bromo-2-amino-allyl benzoate prepared in Example 3 as a raw material, with a
yield of 88.2% and a purity of 88.2%. 99.7%.
Preparation of compounds of formula VI
Example 5: Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane

235.5kg of 5-bromo-2-chlorobenzoic acid was added to 600kg of dichloromethane, then 2kg of DMF was
added, the reaction temperature was controlled to 5-30°C, 130kg of oxalyl chloride was added dropwise, and
after the dropwise addition was completed, the mixture was stirred and dissolved. Atmospheric distillation to
recover dichloromethane for use in the next batch of this step. After steaming, 200kg of dichloromethane was
added to obtain an acid chloride solution, which was stirred and dissolved to be clear for use.
1000kg of dichloromethane, 133kg of anhydrous aluminum trichloride and 123kg of phenethyl ether were
added to the reaction kettle, and the reaction temperature was controlled at -10 to 10°C, and the
dichloromethane solution of the acid chloride prepared above was added dropwise. 10kg of drinking water was
added to quench the reaction, and aluminum trichloride hydrate was precipitated, filtered and recovered. The
filtrate is washed twice with 150kg×2 drinking water, and dichloromethane is recovered at normal pressure,
which can be reused after dehydration. Then in the concentration kettle, add 600kg of 95% ethanol and heat to
dissolve the clear, then cool the crystallization, centrifuge at 5-10 DEG C to obtain a wet product, and dry at
45-55 DEG C to obtain the compound of formula V 5-bromo-2-chloro-4'- Ethoxybenzophenone 279.2kg, yield
82.4%, purity 99.8%.
279.2 kg of compound 5-bromo-2-chloro-4'-ethoxybenzophenone of formula V was added to 600 kg of
methanol, 30 kg of sodium borohydride was added in batches, and after the addition was completed, the
temperature was controlled at 10-30 °C and stirred for 1 h, then Add 10kg of aluminum trichloride, heat to 55-
64° C. and react for 6-8 hours. After the reaction is completed, methanol is recovered under reduced pressure,
which can be reused in this step. After steaming, add 450kg of ethyl acetate, wash with 120kg×2 of tap water,
separate the layers, and concentrate the organic phase to dryness. The solvent can be reused in this step. Add
375kg of methanol, heat at 45-55°C to dissolve the clear liquid, then cool down for crystallization, centrifuge,
and dry under reduced pressure at 27-32°C to dryness to obtain 249.0kg of the compound of formula VI 5-
bromo-2-chloro-4'-ethoxydi Benzylmethane, yield 93.0%, purity 99.9%.
Example 6: Preparation of (3S)-3-[4-[(5-bromo-2-chlorophenyl)methyl]phenoxy]tetrahydrofuran

141.3 kg of 5-bromo-2-chlorobenzoic acid was added to 300 kg of dichloromethane, the reaction
temperature was controlled from -5 to 25° C., 78 kg of thionyl chloride was added dropwise, and the mixture 
was stirred and dissolved. Atmospheric distillation to recover dichloromethane for use in the next batch of this
step. After steaming, 150kg of dichloromethane was added to obtain an acid chloride solution, which was
stirred and dissolved to be clear for use.
600kg of methylene chloride, 80kg of anhydrous aluminium trichloride and 98.0kg (3S)-
phenoxytetrahydrofuran are added to the reactor, the temperature of reaction is controlled to -10-10°C, and the
methylene chloride solution of the above-prepared acid chloride is added dropwise, After dripping, stir for 1-
2h. 6.0 kg of drinking water was added to quench the reaction, and aluminum trichloride hydrate was
precipitated, filtered and recovered. The filtrate is washed twice with 900kg×2 drinking water, and
dichloromethane is recovered at normal pressure, which can be reused after dehydration. Then in the
concentration kettle, add 360kg of methanol and heat to dissolve, then cool down for crystallization, centrifuge
at 0-10°C to obtain a wet product, and dry at 40-50°C to obtain compound (R)-3-(4-(2-chloroform of formula
V) -5-iodobenzoyl)phenoxy)tetrahydrofuran 185.2kg, yield 81.0%, purity 99.7%.
185.2kg of formula V compound (R)-3-(4-(2-chloro-5-iodobenzoyl)phenoxy)tetrahydrofuran was added
to 420kg of methanol, 18.0kg of sodium borohydride was added in batches, the addition was completed, and
the mixture was controlled. Stir at 10-30°C for 1.5h, then add 15kg of boron trifluoride ether, heat to 50-64°C
and react for 5-7h, after the reaction, recover methanol under reduced pressure, which can be reused in this
step. After steaming, add 300kg of toluene, wash with 70kg×2 tap water, separate the liquids, and concentrate
the organic phase to dryness. The solvent can be reused in this step. Add 220kg of methanol and 10kg of
purified water, heat at 45-64°C to dissolve the clear, then cool down for crystallization, centrifuge, and dry
under reduced pressure at 35-40°C to dryness to obtain 162.7kg of compound of formula VI (3S)-3-[4-[( 5-
Bromo-2-chlorophenyl)methyl]phenoxy]tetrahydrofuran, yield 91.2%, purity 99.8%.
Example 7: Preparation of Dapagliflozin (Dapagliflozin)
Using the 5-bromo-2-chloro-4'-ethoxydiphenylmethane obtained above, with reference to the method of
the embodiment of patent application WO03099836A1, dapagliflozin was prepared, and the steps were as
follows:

Synthesis of compounds of formula VIII:
Add 120g of compound of formula VI, 330g of tetrahydrofuran, 600g of toluene into the reaction flask,
start stirring, cool down to -70°C, control the inner temperature ≤-70°C, add 150ml n-butyllithium dropwise,
keep the temperature for 30-60 minutes after dripping, and slowly rotate Into the reaction flask containing
185g of the compound of formula XI (refer to the method of step C of the embodiment of WO03099836A1)
and 640g of toluene, control the internal temperature≤-70 ℃, continue to keep stirring for 3-4 hours, the
reaction is completed, add 55g Quench with methanesulfonic acid and 600 g methanol solution and stir
overnight. Aqueous sodium carbonate solution was added to adjust pH=6-7, the layers were separated, the
organic layer was washed with water, and concentrated to dryness to obtain 130.5 g of the compound of
formula VIII with a yield of 80.6% and a purity of 95.1%.
Synthesis of compounds of formula IX:
114.4 g of the compound of formula VIII, 1200 g of toluene, and 139 g of triethylamine were added to the
reaction flask, stirring was started, and the temperature was lowered to 0°C. Add 217.5 g of acetic anhydride,
keep the temperature for 30 minutes, turn off the cooling, and stir overnight. After the reaction is completed,
add 270g 85%H 3
PO 4
H prepared with 800g tap water 3
PO 4
The solution was diluted, stirred for 30 minutes,
separated into layers, the aqueous layer was extracted twice with 130g×2 toluene, the organic layers were
combined, washed with 150g tap water, separated into layers, and the organic layer was concentrated to
dryness to obtain 150.6g of the compound of formula IX, yield 95.2%, Purity 97.5%.
Synthesis of compounds of formula X:
140 g of the compound of formula IX and 800 g of acetonitrile were added to the reaction flask, stirring
was started, and the temperature was lowered to 0°C. 60.8 g of triethylsilane and 48 g of boron trifluoride
ether were added, the temperature was maintained for 1 hour, the temperature was raised to room temperature,
36 g of triethylsilane and 20 g of boron trifluoride ether were added, and the mixture was stirred overnight.
After the reaction was completed, 800 g of ethyl acetate was added to extract the material, washed with
saturated sodium bicarbonate solution and tap water successively, filtered, and the organic phase was

concentrated to dryness under reduced pressure. Add 560 g of ethanol, heat up to 65-75° C. and stir to dissolve
the solution, turn off the heating, stir overnight, filter and dry to obtain 109.8 g of product with a yield of
82.5% and a purity of 99.4%.
Synthesis of Dapagliflozin:
Add 80 g of the compound of formula X, 200 g of tetrahydrofuran, 400 g of methanol, and 150 g of tap
water to the reaction flask, start stirring, add 7.2 g of lithium hydroxide monohydrate, and stir at room
temperature for 8 hours. After the reaction was completed, the organic solvent was evaporated by
concentration under reduced pressure, dissolved in 700 g of ethyl acetate, washed with 200 g of water,
separated, and the organic phase was concentrated to dryness under reduced pressure to obtain 54.2 g of
dapagliflozin with a yield of 95.6% and a purity of 99.8%.


CN113773194 2021 5-Bromo-2-Chloro-Benzoic Acid As Raw Material For Hypoglycemic Drug Synthesis

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3/23/22, 11:58 AM CN113773194 Preparation method of 5-bromo-2-chloro-benzoic acid as raw material for hypoglycemic drug synthesis

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1. CN113773194 - THE PREPARATION METHOD OF 5-

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Preparation method of 5-bromo-2-chloro-benzoic

Example 2: Benzyl 5-bromo-2-amino-benzoate

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