CN117285411A - Preparation method of 2' -bromo-o-fluoro acetophenone - Google Patents
Preparation method of 2' -bromo-o-fluoro acetophenone Download PDFInfo
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- CN117285411A CN117285411A CN202311162831.4A CN202311162831A CN117285411A CN 117285411 A CN117285411 A CN 117285411A CN 202311162831 A CN202311162831 A CN 202311162831A CN 117285411 A CN117285411 A CN 117285411A
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- fluoro acetophenone
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- NDOMRYSMTMVOIJ-UHFFFAOYSA-N 1-(6-bromo-6-fluorocyclohexa-2,4-dien-1-yl)ethanone Chemical compound FC1(C(C=CC=C1)C(C)=O)Br NDOMRYSMTMVOIJ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- QMATYTFXDIWACW-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1F QMATYTFXDIWACW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 18
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 150000001728 carbonyl compounds Chemical group 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 238000005422 blasting Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000005070 sampling Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000007864 aqueous solution Substances 0.000 abstract description 5
- 238000005893 bromination reaction Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000002140 halogenating effect Effects 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 4
- 229950003825 vonoprazan Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002085 enols Chemical group 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 2
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 2' -bromo-o-fluoro acetophenone, which takes dibromohydantoin as a halogenating agent, and carries out bromination reaction of alpha position of carbonyl compound by adding a catalyst and increasing reaction temperature, thereby successfully replacing the use of liquid bromine. Meanwhile, aiming at the characteristic that products easily generate a large amount of o-fluoro acetophenone and 2 '-dibromo-o-fluoro acetophenone at high temperature, the process of crystallizing the isopropyl alcohol aqueous solution is adopted to prepare the high-purity 2' -dibromo-o-fluoro acetophenone. The method has the advantages of low cost of raw materials, short reaction time, high product purity and the like, is very friendly to the environment, and meets the requirements of green chemical technology.
Description
Technical Field
The invention relates to the technical field of synthesis of medical compounds, in particular to a preparation method of 2' -bromo-o-fluoro acetophenone.
Background
2' -bromo-o-fluoroacetophenone, english name: 2-bromoo-2' -fluoroacetophenone, CAS: [655-15-2], boiling point 61-63 ℃/0.03Torr; the melting point is 25-27 ℃, and the chemical structural formula is as follows:
2' -bromo-o-fluoroacetophenone is a key intermediate of Wu Tianxin drug voronoi. Vonoprazan (Vonopra zanfumarate) is a potassium competitive acid blocker developed by the Wuta Clara, japan, marketed in Japan at 12.26.2014 under the trade name Takecab for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, and helicobacter pylori eradication. Vonoprazan is a new medicine for treating gastrointestinal diseases, has few administration and good medicine effect, is incomparable with other similar medicines so far, and has good market prospect.
The synthetic route of 2' -bromo-o-fluoro acetophenone in the prior art is as follows:
CN106431871a discloses a preparation method of 2' -bromo-o-fluoro acetophenone, which comprises the following technical scheme: the raw materials of o-fluoro acetophenone and methyl tertiary butyl ether are added into a reaction vessel, NBS is added in batches in the presence of a catalyst of aluminum trichloride to prepare 2' -bromo-o-fluoro acetophenone, and finally the product is distilled under reduced pressure, so that the yield is about 80%. In the chemical principle, the solvent methyl tertiary butyl ether, NBS and bromine are contraindicated matters, the decomposition heat risk of the solvent exists, methyl bromide gas is generated, and the potential safety hazard of the process is large and is not suitable for production.
WO 2003/76505 A1 and US2009/156642A1 both dissolve o-fluoro acetophenone in a large amount of acetic acid solvent, and add bromine dropwise to obtain 2' -bromo-o-fluoro acetophenone, which generates a molecule of hydrogen bromide in the reaction, resulting in troublesome post-treatment and serious corrosion to equipment.
Bromine is a second type of easily-made chemicals, which are very inconvenient to use, transport and store in factories, so that the use of bromine is not an ideal process, and a more safe and efficient brominating reagent needs to be sought, and the reaction equation is as follows:
in conclusion, the production method of the 2' -bromo-o-fluoro acetophenone, which has low development cost and accords with the process green industrialization, greatly reduces the production cost of new drugs, improves the accessibility of the drugs for the masses and has very important significance.
Disclosure of Invention
The invention aims to provide a preparation method of 2' -bromo-o-fluoro acetophenone, which has the advantages of low raw material cost, short reaction time, high product purity and yield and the like, is very environment-friendly, and meets the requirements of green chemical process.
For this purpose, the technical scheme of the invention is as follows:
the preparation process of 2' -bromo-o-fluoro acetophenone includes the following chemical reaction equation:
the method comprises the following steps: heating o-fluoro acetophenone and catalyst in solvent to 30-70 deg.c, adding dibromohydantoin in batches, and brominating alpha position of carbonyl compound to obtain 2' -bromo o-fluoro acetophenone.
The sources and theoretical basis of the innovative technical process of the invention are described in detail below, aiming at the drawbacks of the existing synthetic processes.
The rational use of chemicals, green chemistry to reduce hazardous substances and environmental pollution is becoming a hotspot and leading edge of current chemical research, and it is necessary to review and think again with new perspectives for organic halogenation reactions, one of the most-historic basic reactions in organic chemistry. Organic halides, on the one hand, are a useful class of compounds that are widely used and play an important role. Other reagents commonly used for halogenation reactions, and sites where research and production of the halogenation reactions are conducted, are often important monitoring objects of government safety production authorities.
By looking up a new method for alpha-bromination of acetophenone of similar structure, gao Guorui et al in the core journal of organic chemistry 2007 (01) report a new method for synthesizing alpha-bromoacetophenone using 1, 3-dibromo-5, 5-dimethylhydantoin and p-toluenesulfonic acid in methanol and under mild conditions of 20 to 50 c, while no reaction occurs with ortho-nitroacetophenone having electron withdrawing under the same conditions.
The reaction mechanism process is as follows:
according to the alpha-bromo reaction mechanism of acetophenone described in the literature, the raw material o-fluoro acetophenone used in the invention also greatly influences the interconversion process due to the electron-withdrawing effect of fluorine atoms, and the steric hindrance of the o-fluoro atoms can be considered to prevent the conversion of keto form and enol form, so that the reaction is difficult to carry out. In terms of reaction thermodynamics, the reaction temperature is increased or a Lewis catalyst is added, so that the activation energy of the reaction can be reduced, the enol conversion yield can be accelerated, and the reaction can be smoothly carried out.
In addition, the inventors found that the stability of 2 '-bromoo-fluoroacetophenone at high temperature was poor, and that o-fluoroacetophenone and 2' -dibromoo-fluoroacetophenone were easily produced, resulting in poor purity of the distilled product, when the post-treatment distillation of patent CN106431871a was repeated.
The possible equations are:
through a great deal of experimental study, the inventor finds that dibromohydantoin is taken as a halogenating reagent from the green chemistry point of view, and the bromination reaction of the alpha position of the carbonyl compound is smoothly carried out by adding a catalyst and increasing the reaction temperature, so that the use of liquid bromine is successfully replaced. Meanwhile, aiming at the characteristic that products easily generate a large amount of o-fluoro acetophenone and 2 '-dibromo-o-fluoro acetophenone at high temperature, the invention adopts the process of crystallizing isopropanol water solution to prepare the high-purity 2' -dibromo-o-fluoro acetophenone, thereby forming the current preparation process.
Further, the method specifically comprises the following steps:
s1: under the protection of nitrogen, adding o-fluoro acetophenone, a catalyst and a solvent, starting stirring, controlling the temperature to be 30-70 ℃, adding dibromohydantoin in batches, after the stirring is finished for 1 hour, starting sampling and central control, and performing GC control: the o-fluoro acetophenone is less than or equal to 5.00 percent, and the reaction is finished;
s2: and (3) after the solvent is removed from the reaction solution under reduced pressure, adding isopropanol and water, stirring and heating, continuously stirring for 30min after dissolving, cooling to-5 to-10 ℃, standing for 2 hours after crystals are separated out, filtering to obtain white solid, and drying to constant weight by blasting at room temperature.
Further, the catalyst is cuprous chloride, cuprous bromide, anhydrous zinc chloride, boron trifluoride diethyl ether and p-toluenesulfonic acid; preferably cuprous bromide.
Further, the reaction temperature is 30-40 ℃.
Further, the solvent is ethyl acetate, methanol, acetonitrile, methyl tertiary butyl ether, dichloromethane, preferably dichloromethane.
The invention has the beneficial effects that:
1. the inventors found that the use of liquid bromine was successfully replaced by performing bromination reaction of the alpha position of a carbonyl compound by adding a catalyst and increasing the reaction temperature with dibromohydantoin as a halogenating agent from the viewpoint of green chemistry. Meanwhile, aiming at the characteristic that products easily generate a large amount of o-fluoro acetophenone and 2 '-dibromo-o-fluoro acetophenone at high temperature, the process of crystallizing the isopropyl alcohol aqueous solution is adopted to prepare the high-purity 2' -dibromo-o-fluoro acetophenone.
2. The method has the advantages of low raw material cost, short reaction time, high product purity and yield and the like, is very friendly to the environment, and meets the requirements of green chemical technology.
Drawings
FIG. 1 is a GC spectrum of the purity of 2' -bromoo-fluoroacetophenone of example 1.
Detailed Description
The following examples will help the scientific researchers understand the technical gist of the present invention, but are not intended to limit the scope of the present invention.
Example 1
Adding 100.0g of o-fluoro acetophenone, 4.5g of cuprous bromide and 600ml of dichloromethane into a reaction kettle, starting stirring, protecting by nitrogen, slowly heating to 30-40 ℃, adding 121.1g of dibromohydantoin, keeping the reaction for 6 hours, adding 1g of sodium dithionite, slowly cooling to 30 ℃, adding 300ml of water, and separating the water at the lower layer; the solvent methylene dichloride is removed under reduced pressure, 140.0g of 60% isopropanol water solution is added, the temperature is raised for dissolving, then the temperature is reduced for crystallization, 130.5g of product is obtained through filtration, the GC purity is 99.24%, and the yield is 83.06%.
Example 2
Adding 100.0g of o-fluoro acetophenone, 4.3g of cuprous bromide and 600ml of methanol into a reaction kettle, starting stirring, slowly heating to 45-50 ℃ under the protection of nitrogen, adding 121.1g of dibromohydantoin, keeping the reaction for 6 hours, adding 1g of sodium dithionite, slowly cooling to 30 ℃, removing methanol under reduced pressure, adding 140.0g of 60% isopropyl alcohol aqueous solution, heating to dissolve, cooling again for crystallization to obtain a white solid crude product, adding equal volumes of dichloromethane and water for removing salt, recycling dichloromethane, and obtaining 124.7g of a product, wherein the GC purity is 98.64%, and the yield is 79.39%.
Example 3
Adding 100.0g of o-fluoro acetophenone, 4.3g of cuprous chloride and 600ml of dichloromethane into a reaction kettle, starting stirring, protecting by nitrogen, slowly heating to 30-40 ℃, adding 121.1g of dibromohydantoin, keeping the reaction for 6 hours, adding 1g of sodium dithionite, adding 300ml of water, separating the water at the lower layer, removing the solvent dichloromethane under reduced pressure, adding 140.0g of 60% isopropanol aqueous solution, heating to dissolve, cooling and crystallizing, filtering to obtain 128.8g of product, wherein the GC purity is 98.94%, and the yield is 81.98%.
Example 4
Adding 100.0g of o-fluoro acetophenone, 37.7g of p-toluenesulfonic acid and 500ml of acetonitrile into a reaction kettle, starting stirring, protecting by nitrogen, slowly heating to 45-50 ℃, adding 121.1g of dibromohydantoin, keeping the reaction for 20 hours, adding 1g of sodium dithionite, slowly cooling to 30 ℃, removing acetonitrile under reduced pressure, adding 150.0g of 50% isopropyl alcohol aqueous solution, heating to dissolve, cooling and crystallizing to obtain a white solid crude product, adding equal volumes of dichloromethane and water to remove salt, recycling dichloromethane, and obtaining 102.1g of a product, wherein the GC purity is 97.34%, and the yield is 64.9%.
Example 5
Adding 100.0g of o-fluoro acetophenone, 2.6g of anhydrous zinc chloride and 500ml of methyl tertiary butyl ether into a reaction kettle, starting stirring, slowly heating to 50-60 ℃, adding 121.1g of dibromohydantoin, keeping the reaction for 4 hours, adding 1.5g of sodium dithionite, slowly cooling to 30 ℃, adding 300ml of water, stirring and standing, separating a water layer, removing a solvent from an organic layer under reduced pressure, adding 80.0g of 60% isopropanol water solution, heating to dissolve, cooling again for crystallization, filtering to obtain 113.2g of a product, wherein the GC purity is 87.85%, and the yield is 72.1%.
Example 6
Adding 100.0g of o-fluoro acetophenone, 1.6g of boron trifluoride diethyl etherate solution and 500ml of ethyl acetate into a reaction kettle, starting stirring, slowly heating to 50-60 ℃, adding 121.2g of dibromohydantoin, keeping the reaction for 4 hours, adding 1.5g of sodium dithionite, slowly cooling to 30 ℃, adding 300ml of water, stirring and standing, separating a water layer, removing a solvent from an organic layer under reduced pressure, adding 80.0g of 60% isopropanol water solution, heating to dissolve, cooling again for crystallization, filtering to obtain 105.3g of a product, wherein the GC purity is 87.85%, and the yield is 67.0%.
Comparative example 1
The technical scheme described in CN106431871a is repeated:
50.0g of o-fluoro acetophenone, 0.5g of anhydrous aluminum chloride and 100ml of methyl tertiary butyl ether are added into a reaction kettle, stirring is started, nitrogen protection is carried out, the temperature is slowly increased to 45-50 ℃, 75.0g of NBS is added, the reaction is kept for 8 hours, the temperature is slowly reduced to 30 ℃, 200ml of water is added into the reactant, the byproducts are washed, an oil layer (lower layer) is separated, the oil layer is rectified under reduced pressure, and a fraction of 82-84 ℃ (5 mmHg) is collected, thus 58.9g of product with GC purity 78.92% and yield of 74.9% are obtained.
The data prove that the yield and the content of the prior synthesis technology are very low, which accords with the explanation of theoretical knowledge of o-fluoro acetophenone, and the product is easy to be converted into dibromo impurities, raw materials and the like at high temperature.
The invention is not limited to the above embodiments, and based on the technical solution disclosed in the invention, a person skilled in the art may make some substitutions and modifications to some technical features thereof without creative effort according to the technical content disclosed, and all the substitutions and modifications are within the protection scope of the invention.
Claims (5)
1. The preparation method of the 2' -bromo-o-fluoro acetophenone is characterized by comprising the following chemical reaction equation:
the method comprises the following steps: heating o-fluoro acetophenone and catalyst in solvent to 30-70 deg.c, adding dibromohydantoin in batches, and brominating alpha position of carbonyl compound to obtain 2' -bromo o-fluoro acetophenone.
2. The preparation method of 2' -bromo-o-fluoro acetophenone according to claim 1, which is characterized by comprising the following steps:
s1: under the protection of nitrogen, adding o-fluoro acetophenone, a catalyst and a solvent, starting stirring, controlling the temperature to be 30-70 ℃, adding dibromohydantoin in batches, after the stirring is finished for 1 hour, starting sampling and central control, and performing GC control: the o-fluoro acetophenone is less than or equal to 5.00 percent, and the reaction is finished;
s2: and (3) after the solvent is removed from the reaction solution under reduced pressure, adding isopropanol and water, stirring and heating, continuously stirring for 30min after dissolving, cooling to-5 to-10 ℃, standing for 2 hours after crystals are separated out, filtering to obtain white solid, and drying to constant weight by blasting at room temperature.
3. The method for preparing 2' -bromoo-fluoro acetophenone according to claim 2, wherein the catalyst is cuprous chloride, cuprous bromide, anhydrous zinc chloride, boron trifluoride diethyl ether or p-toluene sulfonic acid; preferably cuprous bromide.
4. The process for preparing 2' -bromoo-fluoroacetophenone according to claim 2, wherein the reaction temperature in step S1 is from 30 to 40 ℃.
5. The method for preparing 2' -bromo-o-fluoro acetophenone according to claim 1, wherein the solvent is ethyl acetate, methanol, acetonitrile, methyl t-butyl ether and/or dichloromethane; preferably dichloromethane.
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| CN202311162831.4A CN117285411A (en) | 2023-09-11 | 2023-09-11 | Preparation method of 2' -bromo-o-fluoro acetophenone |
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| CN202311162831.4A CN117285411A (en) | 2023-09-11 | 2023-09-11 | Preparation method of 2' -bromo-o-fluoro acetophenone |
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| CN117003727A (en) * | 2022-12-30 | 2023-11-07 | 上海毕臣生化科技有限公司 | Preparation method of 4, 5-dibromo-3-chlorothiophene-2-formic acid |
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