CN111620778A - Preparation method of 5-bromo-2-chlorobenzoic acid - Google Patents
Preparation method of 5-bromo-2-chlorobenzoic acid Download PDFInfo
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- CN111620778A CN111620778A CN202010468779.5A CN202010468779A CN111620778A CN 111620778 A CN111620778 A CN 111620778A CN 202010468779 A CN202010468779 A CN 202010468779A CN 111620778 A CN111620778 A CN 111620778A
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- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000003054 catalyst Substances 0.000 claims abstract description 58
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 23
- 230000007062 hydrolysis Effects 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 18
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims abstract description 16
- 229910021575 Iron(II) bromide Inorganic materials 0.000 claims abstract description 15
- 229940046149 ferrous bromide Drugs 0.000 claims abstract description 15
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 claims abstract description 15
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims abstract description 14
- QNUPENXMUJPLDQ-UHFFFAOYSA-M cyclopenta-1,3-diene;cyclopenta-1,3-dien-1-ylmethyl(trimethyl)azanium;iron(2+);bromide Chemical compound [Fe+2].[Br-].C=1C=C[CH-]C=1.C[N+](C)(C)CC1=CC=C[CH-]1 QNUPENXMUJPLDQ-UHFFFAOYSA-M 0.000 claims abstract description 14
- JORHQXXXJVNQAL-UHFFFAOYSA-N 4-bromo-1-chloro-2-(trichloromethyl)benzene Chemical compound ClC1=C(C=C(C=C1)Br)C(Cl)(Cl)Cl JORHQXXXJVNQAL-UHFFFAOYSA-N 0.000 claims abstract description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 10
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000013329 compounding Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- -1 N-bromoimide Chemical compound 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 230000008901 benefit Effects 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 6
- 208000012839 conversion disease Diseases 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 10
- CHIMDMPJABIKAI-UHFFFAOYSA-N 5-bromocyclopenta-1,3-diene;cyclopenta-1,3-diene;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.BrC1=CC=C[CH-]1 CHIMDMPJABIKAI-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 description 1
- ZUNCHZBITMUSRD-UHFFFAOYSA-N 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene Chemical compound C1=CC(OCC)=CC=C1CC1=CC(Br)=CC=C1Cl ZUNCHZBITMUSRD-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004153 Potassium bromate Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940094037 potassium bromate Drugs 0.000 description 1
- 235000019396 potassium bromate Nutrition 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical group S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
- C07C63/70—Monocarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- C07C2527/24—Nitrogen compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- C07C2531/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups C07C2531/02 - C07C2531/24
- C07C2531/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups C07C2531/02 - C07C2531/24 of the platinum group metals, iron group metals or copper
- C07C2531/30—Halides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation method of 5-bromo-2-chlorobenzoic acid, which is characterized by comprising the following steps: reacting 2-chlorotrifluoromethane serving as a raw material with a brominating agent under the catalysis of a first catalyst to generate 2-chloro-5-bromotrichlorotoluene, adding water and a hydrolysis catalyst into the 2-chloro-5-bromotrichlorotoluene, and performing post-treatment and purification to obtain 5-bromo-2-chlorobenzoic acid; the first catalyst is prepared by compounding ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide. The invention also discloses the 5-bromo-2-chlorobenzoic acid prepared by the preparation method of the 5-bromo-2-chlorobenzoic acid. The preparation method of 5-bromo-2-chlorobenzoic acid disclosed by the invention has the advantages that the traditional preparation process conditions are optimized and innovated, the product purity, the reaction conversion rate and the production efficiency are effectively improved, the preparation cost is low, the environmental pressure is low, the synthetic route is short, the operation is simple and easy, the discharge of three wastes is reduced, and the reaction yield is high.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of 5-bromo-2-chlorobenzoic acid.
Background
The SGLT-2 inhibitor is a new-generation diabetes drug, controls blood sugar by inhibiting the reabsorption of glucose in the kidney, has unique action mechanism, does not depend on the dysfunction of beta cells or the degree of insulin resistance, has no effect reduction along with the function failure of the beta cells or serious insulin resistance, does not generate adverse reaction brought by the traditional drugs, has various clinical advantages, and particularly has the advantage of reducing cardiovascular risk clinically. The 5-bromo-2-chlorobenzoic acid is a common key intermediate for synthesizing a novel antidiabetic SGLT-2 inhibitor, so that the search for a proper preparation method of the 5-bromo-2-chlorobenzoic acid is particularly important.
The synthesis methods of 5-bromo-2-chlorobenzoic acid reported at present mainly comprise the following two methods: the synthesis route of 5-bromo-2-chlorobenzoic acid reported in patent CN1740135 is that starting from 5-bromo-2-chlorotrifluoromethane, heating and hydrolyzing in fuming sulfuric acid, then adding the reaction solution into crushed ice to separate out a crude product, and recrystallizing the crude product with toluene to obtain a product. The sulfuric acid added in the route is much and cannot be recovered; and a large amount of fluorine-containing wastewater is generated, and the treatment is difficult. In addition, the starting materials used in this synthetic route are very expensive. It is clear that this route is clearly not an ideal commercial route. In Amalendu B.Gopa l C h.etc. of bromine of halo benzenes and halo benzoic acids J.Indian chem.Soc.1980,57(6), 640-642, 2-chlorobenzoic acid is used as a raw material, and is brominated by respectively adopting a potassium bromate system and a sodium bromide system to prepare the 5-bromo-2-chlorobenzoic acid. However, the final yield of this synthesis method is low, only 40%.
In order to solve the problems to be solved by researchers in the industry, chinese patents with No. CN105622382B and No. CN107162894A disclose that 5-bromo-2-chlorobenzoic acid is obtained by bromination and strong acid hydrolysis reaction using 2-chlorotrifluoromethylene as a raw material. The reaction needs two-step synthesis, and strong acids such as sulfuric acid are used in the hydrolysis reaction, so that more strong-acid wastewater is generated, and the reaction is not environment-friendly.
Therefore, how to efficiently and quickly synthesize the 5-bromo-2-chlorobenzoic acid with high yield and purity is crucial to promoting the wide application of the SGLT-2 inhibitor in the treatment of diabetes.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of 5-bromo-2-chlorobenzoic acid, which effectively improves the product purity, the reaction conversion rate and the production efficiency by optimizing and innovating the traditional preparation process conditions, has low preparation cost, small environmental pressure, short synthetic route, simple and easy operation, reduces the discharge of three wastes and has high reaction yield.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of 5-bromo-2-chlorobenzoic acid is characterized by comprising the following steps: reacting 2-chlorotrifluoromethane serving as a raw material with a brominating agent under the catalysis of a first catalyst to generate 2-chloro-5-bromotrichlorotoluene, adding water and a hydrolysis catalyst into the 2-chloro-5-bromotrichlorotoluene, and performing post-treatment and purification to obtain 5-bromo-2-chlorobenzoic acid; the first catalyst is prepared by compounding ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide.
Preferably, the brominating reagent is at least one of bromine, N-bromoimide and tetrabutylammonium bromide.
Preferably, the first catalyst is ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and bromoferrocene, and the mass ratio of the ferric bromide to the copper bromide to the ferrocene bromide is 1:1 (0.1-0.3) to 0.3-0.6.
Preferably, the hydrolysis catalyst is at least one of sulfamic acid, glycolic acid, citric acid and ethylenediamine tetraacetic acid.
Preferably, the molar ratio of the 2-chlorotrifluoromethane, the brominating agent, the first catalyst, the water and the hydrolysis catalyst is 1:1 (0.2-0.4) to (60-90) to (3-5).
Preferably, the preparation method of the 5-bromo-2-chlorobenzoic acid comprises the following steps: the 2-trichloro toluene, the brominating agent and the first catalyst are mixed and catalyzed, stirred and reacted for 15-24 hours at the temperature of 20-60 ℃, then water and the hydrolysis catalyst are added, stirred and reacted for 8-12 hours at the temperature of 80-160 ℃, then the mixed solvent is added to wash the product for 3-8 times, and then the product is dried in a vacuum drying oven at the temperature of 80-90 ℃ to constant weight, so that the 5-bromo-2-chlorobenzoic acid is obtained.
Preferably, the mixed solvent is formed by mixing an alcohol solvent and water according to the mass ratio of 1 (2-4).
Preferably, the alcohol solvent is at least one of ethanol, methanol, glycerol and isopropanol.
The invention also aims to provide 5-bromo-2-chlorobenzoic acid prepared according to the preparation method of 5-bromo-2-chlorobenzoic acid.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: according to the preparation method of 5-bromo-2-chlorobenzoic acid, provided by the invention, the traditional preparation process conditions are optimized and innovated, so that the product purity, the reaction conversion rate and the production efficiency are effectively improved, the preparation cost is low, the environmental pressure is low, the synthetic route is short, the operation is simple and easy, the discharge of three wastes is reduced, and the reaction yield is high. The method has the advantages of simplifying the catalyst and reaction steps, realizing one-pot boiling, omitting intermediate complicated intermediate purification and post-treatment processes, synthesizing the 5-bromo-2-chlorobenzoic acid in one step by effectively controlling reaction conditions, charging sequence and proportion, along with low discharge of three wastes, good solvent recovery effect and low production cost.
Detailed Description
A preparation method of 5-bromo-2-chlorobenzoic acid is characterized by comprising the following steps: reacting 2-chlorotrifluoromethane serving as a raw material with a brominating agent under the catalysis of a first catalyst to generate 2-chloro-5-bromotrichlorotoluene, adding water and a hydrolysis catalyst into the 2-chloro-5-bromotrichlorotoluene, and performing post-treatment and purification to obtain 5-bromo-2-chlorobenzoic acid; the first catalyst is prepared by compounding ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide.
Preferably, the brominating reagent is at least one of bromine, N-bromoimide and tetrabutylammonium bromide.
Preferably, the first catalyst is prepared by mixing ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and bromoferrocene according to the mass ratio of 1:1 (0.1-0.3) to (0.3-0.6) to 0.1.
Preferably, the hydrolysis catalyst is at least one of sulfamic acid, glycolic acid, citric acid and ethylenediamine tetraacetic acid.
Preferably, the molar ratio of the 2-chlorotrifluoromethane, the brominating agent, the first catalyst, the water and the hydrolysis catalyst is 1:1 (0.2-0.4) to (60-90) to (3-5).
Preferably, the preparation method of the 5-bromo-2-chlorobenzoic acid comprises the following steps: the 2-trichloro toluene, the brominating agent and the first catalyst are mixed and catalyzed, stirred and reacted for 15-24 hours at the temperature of 20-60 ℃, then water and the hydrolysis catalyst are added, stirred and reacted for 8-12 hours at the temperature of 80-160 ℃, then the mixed solvent is added to wash the product for 3-8 times, and then the product is dried in a vacuum drying oven at the temperature of 80-90 ℃ to constant weight, so that the 5-bromo-2-chlorobenzoic acid is obtained.
Preferably, the mixed solvent is formed by mixing an alcohol solvent and water according to the mass ratio of 1 (2-4).
Preferably, the alcohol solvent is at least one of ethanol, methanol, glycerol and isopropanol.
The invention also aims to provide 5-bromo-2-chlorobenzoic acid prepared according to the preparation method of 5-bromo-2-chlorobenzoic acid.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: according to the preparation method of 5-bromo-2-chlorobenzoic acid, provided by the invention, the traditional preparation process conditions are optimized and innovated, so that the product purity, the reaction conversion rate and the production efficiency are effectively improved, the preparation cost is low, the environmental pressure is low, the synthetic route is short, the operation is simple and easy, the discharge of three wastes is reduced, and the reaction yield is high. The method has the advantages of simplifying the catalyst and reaction steps, realizing one-pot boiling, omitting intermediate complicated intermediate purification and post-treatment processes, synthesizing the 5-bromo-2-chlorobenzoic acid in one step by effectively controlling reaction conditions, charging sequence and proportion, along with low discharge of three wastes, good solvent recovery effect and low production cost.
The invention will be further described with reference to specific examples, but the scope of protection of the invention is not limited thereto:
example 1
Embodiment 1 provides a method for preparing 5-bromo-2-chlorobenzoic acid, which is characterized by comprising the following steps: reacting 2-chlorotrifluoromethane serving as a raw material with a brominating agent under the catalysis of a first catalyst to generate 2-chloro-5-bromotrichlorotoluene, adding water and a hydrolysis catalyst into the 2-chloro-5-bromotrichlorotoluene, and performing post-treatment and purification to obtain 5-bromo-2-chlorobenzoic acid; the first catalyst is prepared by compounding ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide.
The brominating reagent is bromine; the first catalyst is prepared by mixing ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and bromoferrocene according to the mass ratio of 1:1:0.1:0.3: 0.1; the hydrolysis catalyst is sulfamic acid.
The molar ratio of the 2-chlorotrifluoromethane to the brominating agent to the first catalyst to the water to the hydrolysis catalyst is 1:1:0.2:60: 3.
The preparation method of the 5-bromo-2-chlorobenzoic acid comprises the following steps: catalytically mixing 2-chlorotrifluoromethane, a brominating agent and a first catalyst, stirring and reacting for 15 hours at 20 ℃, then adding water and a hydrolysis catalyst, stirring and reacting for 8 hours at 80 ℃, then adding a mixed solvent to wash a product for 3 times, and then placing the product in a vacuum drying oven to dry the product to constant weight at 80 ℃ to obtain 5-bromo-2-chlorobenzoic acid; the mixed solvent is formed by mixing an alcohol solvent and water according to the mass ratio of 1: 2; the alcohol solvent is ethanol.
5-bromo-2-chlorobenzoic acid prepared according to the preparation method of 5-bromo-2-chlorobenzoic acid.
Example 2
Embodiment 2 provides a preparation method of 5-bromo-2-chlorobenzoic acid, which is substantially the same as embodiment 1 except that the first catalyst is prepared by mixing ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide according to a mass ratio of 1:1:0.15:0.4: 0.1; the molar ratio of the 2-chlorotrifluoromethane to the brominating agent to the first catalyst to the water to the hydrolysis catalyst is 1:1:0.25:70: 3.5.
Example 3
Embodiment 3 provides a method for preparing 5-bromo-2-chlorobenzoic acid, which is substantially the same as in embodiment 1, except that the first catalyst is prepared by mixing ferric bromide, ferrous bromide, copper bromide, (ferrocenylmethyl) trimethyl ammonium bromide and bromoferrocene in a mass ratio of 1:1:0.2:0.45: 0.1; the molar ratio of the 2-chlorotrifluoromethane to the brominating agent to the first catalyst to the water to the hydrolysis catalyst is 1:1:0.3:75: 4.
Example 4
Embodiment 4 provides a method for preparing 5-bromo-2-chlorobenzoic acid, which is substantially the same as embodiment 1 except that the first catalyst is prepared by mixing ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide according to a mass ratio of 1:1:0.26:0.55: 0.1; the molar ratio of the 2-chlorotrifluoromethane to the brominating agent to the first catalyst to the water to the hydrolysis catalyst is 1:1:0.35:85: 4.5.
Example 5
Embodiment 5 provides a preparation method of 5-bromo-2-chlorobenzoic acid, which is substantially the same as in embodiment 1, except that the first catalyst is prepared by mixing ferric bromide, ferrous bromide, copper bromide, (ferrocenylmethyl) trimethyl ammonium bromide and bromoferrocene in a mass ratio of 1:1:0.3:0.6: 0.1; the molar ratio of the 2-chlorotrifluoromethane to the brominating agent to the first catalyst to the water to the hydrolysis catalyst is 1:1:0.4:90: 5.
Comparative example 1
Comparative example 1 provides a preparation method of 5-bromo-2-chlorobenzoic acid, which is substantially the same as example 1 except that the first catalyst is a mixture of ferric bromide, ferrous bromide, copper bromide and bromoferrocene in a mass ratio of 1:1:0.1: 0.1.
Comparative example 2
Comparative example 2 provides a preparation method of 5-bromo-2-chlorobenzoic acid, which is substantially the same as example 1 except that the first catalyst is ferric bromide, ferrous bromide, cupric bromide, (ferrocenyl methyl) trimethyl ammonium bromide mixed in a mass ratio of 1:1:0.1: 0.3.
Comparative example 3
Comparative example 3 provides a process for the preparation of 5-bromo-2-chlorobenzoic acid which is essentially the same as example 1 except that the molar ratio of 2-chlorotrifluoromethylene, brominating agent, first catalyst, water, hydrolysis catalyst is 1:1:0.1:50: 2.
5-bromo-2-chlorobenzoic acid was prepared according to the method for preparing 5-bromo-2-chlorobenzoic acid described in examples 1-5 and comparative examples 1-3, and the purity and yield of the product are shown in Table 1.
TABLE 1
| Item | Yield of | Purity of the product |
| Unit of | ％ | ％ |
| Example 1 | 89.5 | 98.8 |
| Example 2 | 91.1 | 99.1 |
| Example 3 | 91.6 | 99.5 |
| Example 4 | 92.0 | 99.7 |
| Example 5 | 92.5 | 99.9 |
| Comparative example 1 | 81.4 | 97.3 |
| Comparative example 2 | 82.2 | 97.5 |
| Comparative example 3 | 80.1 | 97.3 |
As can be seen from Table 1, the process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane disclosed by the examples of the present invention gives higher yields and product purities as a result of the synergistic effect of the steps.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A preparation method of 5-bromo-2-chlorobenzoic acid is characterized by comprising the following steps: reacting 2-chlorotrifluoromethane serving as a raw material with a brominating agent under the catalysis of a first catalyst to generate 2-chloro-5-bromotrichlorotoluene, adding water and a hydrolysis catalyst into the 2-chloro-5-bromotrichlorotoluene, and performing post-treatment and purification to obtain 5-bromo-2-chlorobenzoic acid; the first catalyst is prepared by compounding ferric bromide, ferrous bromide, copper bromide, (ferrocenyl methyl) trimethyl ammonium bromide and ferrocene bromide.
2. The preparation method of 5-bromo-2-chlorobenzoic acid according to claim 1, wherein the brominating reagent is at least one of bromine, N-bromoimide, and tetrabutylammonium bromide.
3. The preparation method of 5-bromo-2-chlorobenzoic acid according to claim 1, wherein the first catalyst is ferric bromide, ferrous bromide, cupric bromide, (ferrocenyl methyl) trimethyl ammonium bromide, and ferrocene bromide, and the mass ratio of the first catalyst to the ferrocene bromide is 1:1 (0.1-0.3) to 0.3-0.6) to 0.1.
4. The method for preparing 5-bromo-2-chlorobenzoic acid according to claim 1, wherein the hydrolysis catalyst is at least one of sulfamic acid, glycolic acid, citric acid and ethylenediamine tetraacetic acid.
5. The method for preparing 5-bromo-2-chlorobenzoic acid according to claim 1, wherein the molar ratio of the 2-chlorotrifluoromethylene, the brominating agent, the first catalyst, water, and the hydrolysis catalyst is 1:1 (0.2-0.4) to (60-90) to (3-5).
6. The method for preparing 5-bromo-2-chlorobenzoic acid according to claim 1, wherein the method for preparing 5-bromo-2-chlorobenzoic acid comprises the following steps: the 2-trichloro toluene, the brominating agent and the first catalyst are mixed and catalyzed, stirred and reacted for 15-24 hours at the temperature of 20-60 ℃, then water and the hydrolysis catalyst are added, stirred and reacted for 8-12 hours at the temperature of 80-160 ℃, then the mixed solvent is added to wash the product for 3-8 times, and then the product is dried in a vacuum drying oven at the temperature of 80-90 ℃ to constant weight, so that the 5-bromo-2-chlorobenzoic acid is obtained.
7. The preparation method of 5-bromo-2-chlorobenzoic acid according to claim 6, wherein the mixed solvent is prepared by mixing an alcohol solvent and water according to a mass ratio of 1 (2-4).
8. The preparation method of 5-bromo-2-chlorobenzoic acid according to claim 7, wherein the alcohol solvent is at least one of ethanol, methanol, glycerol, and isopropanol.
9. 5-bromo-2-chlorobenzoic acid prepared by the process according to any one of claims 1 to 8.
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| CN112979448A (en) * | 2021-03-01 | 2021-06-18 | 苏州小栗医药科技有限公司 | Preparation method of high-selectivity 5-bromo-2-chlorobenzoic acid |
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| US4155940A (en) * | 1977-02-25 | 1979-05-22 | Bayer Aktiengesellschaft | M-Bromo-benzotrifluorides |
| CN105622382A (en) * | 2016-02-23 | 2016-06-01 | 苏州天马精细化学品股份有限公司 | Synthesis method of 5-bromo-2-chloro benzoic acid |
| CN107162894A (en) * | 2017-06-27 | 2017-09-15 | 南通市纳百园化工有限公司 | The post-treatment new process of the chlorobenzoic acid of 5 bromine 2 |
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| US4155940A (en) * | 1977-02-25 | 1979-05-22 | Bayer Aktiengesellschaft | M-Bromo-benzotrifluorides |
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| CN107162894A (en) * | 2017-06-27 | 2017-09-15 | 南通市纳百园化工有限公司 | The post-treatment new process of the chlorobenzoic acid of 5 bromine 2 |
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| CN112979448A (en) * | 2021-03-01 | 2021-06-18 | 苏州小栗医药科技有限公司 | Preparation method of high-selectivity 5-bromo-2-chlorobenzoic acid |
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