CN114573534A - Preparation method of 5-bromobenzofuranone - Google Patents
Preparation method of 5-bromobenzofuranone Download PDFInfo
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- CN114573534A CN114573534A CN202210326663.7A CN202210326663A CN114573534A CN 114573534 A CN114573534 A CN 114573534A CN 202210326663 A CN202210326663 A CN 202210326663A CN 114573534 A CN114573534 A CN 114573534A
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- China
- Prior art keywords
- bromo
- reaction
- ethanone
- hydroxyphenyl
- bromobenzofuranone
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- QIPSJPXUPBXGKI-UHFFFAOYSA-N 5-bromo-3h-1-benzofuran-2-one Chemical compound BrC1=CC=C2OC(=O)CC2=C1 QIPSJPXUPBXGKI-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- FZIUHYVCSFQKFC-UHFFFAOYSA-N 2-bromo-1-(5-bromo-2-hydroxyphenyl)ethanone Chemical compound OC1=CC=C(Br)C=C1C(=O)CBr FZIUHYVCSFQKFC-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000003054 catalyst Substances 0.000 claims abstract description 31
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- HQCCNFFIOWYINW-UHFFFAOYSA-N 1-(5-bromo-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(Br)=CC=C1O HQCCNFFIOWYINW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000005893 bromination reaction Methods 0.000 claims abstract description 24
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 18
- 150000007530 organic bases Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 230000031709 bromination Effects 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 7
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- -1 benzyl ammonium tribromide Chemical compound 0.000 claims description 3
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- AYOVPQORFBWFNO-UHFFFAOYSA-N 5-bromo-1-benzofuran Chemical compound BrC1=CC=C2OC=CC2=C1 AYOVPQORFBWFNO-UHFFFAOYSA-N 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 93
- 239000012071 phase Substances 0.000 description 63
- 239000012043 crude product Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 42
- 238000002390 rotary evaporation Methods 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000002904 solvent Substances 0.000 description 27
- 238000005406 washing Methods 0.000 description 26
- 239000012267 brine Substances 0.000 description 25
- 229960001701 chloroform Drugs 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 239000007787 solid Substances 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000007789 gas Substances 0.000 description 18
- 238000012544 monitoring process Methods 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000001816 cooling Methods 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 239000012046 mixed solvent Substances 0.000 description 13
- 238000001953 recrystallisation Methods 0.000 description 13
- 239000002274 desiccant Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- 238000005086 pumping Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 208000020401 Depressive disease Diseases 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- 229910021576 Iron(III) bromide Inorganic materials 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229960001653 citalopram Drugs 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- XEMRAKSQROQPBR-UHFFFAOYSA-N (trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=CC=C1 XEMRAKSQROQPBR-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical compound CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 description 1
- UXUCDQLDYILHQI-UHFFFAOYSA-N 5-bromo-1-benzofuran-3-one Chemical compound BrC1=CC=C2OCC(=O)C2=C1 UXUCDQLDYILHQI-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 206010027951 Mood swings Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- XODPQKCXGFBFHX-UHFFFAOYSA-M sodium;hydrogen sulfite;hydrate Chemical compound O.[Na+].OS([O-])=O XODPQKCXGFBFHX-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- 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
Abstract
The invention relates to the technical field of synthesis of medical intermediates, and provides a preparation method of 5-bromobenzofuranone. The preparation method provided by the invention comprises the following steps: mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone; and mixing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the organic base and a second organic solvent, and carrying out cyclization reaction to obtain the 5-bromobenzofuranone. The method takes 2-hydroxy-5-bromoacetophenone as a raw material, and prepares the 5-bromobenzofuran by carrying out bromination reaction and cyclization reaction in sequence, and has the advantages of simple operation, high yield and high purity. Furthermore, the raw materials required by the method are easier to obtain, the reaction time is short, and the complexity of the preparation method is more favorably reduced.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of 5-bromobenzofuranone.
Background
Depressive disorder refers to a category of mood disorders characterized by significant and persistent mood swings as the major clinical features due to various causes, and is a chronic mental disease with high morbidity, high recurrence rate and high disability rate, accompanied by cognitive and behavioral changes of different degrees, and some patients have self-injury and suicide behavior. Most of the diseases are acute or subacute, the average onset age is 20-30 years old, almost every age group has the possibility of suffering from depressive disorder, and women are more than men. The average course of a single depressive episode is about 16 weeks, with an average of about 20 weeks after the episode has healed. If left untreated, the course of the disease typically lasts for 6 months or more.
Currently, drug therapy is the primary treatment for depressive disorders. In the treatment medicines, citalopram is used as a 5-hydroxytryptamine reuptake inhibitor (SSRIs), has the advantages of good curative effect, good tolerance and relatively few adverse reactions, is most commonly used in clinic and is also one of the first-line medicines recommended by all the great fingers for treating depression.
5-Bromomofuranone (5-Bromo-3(2H) -benzofuran-one, C8H5BrO2) Is a Y-lactone compound with aromatic structure, which is one of the very important intermediates for synthesizing citalopram. There are many reports in the literature on the synthesis of 5-bromobenzofuranone. In 2001, Safdar Hayat et al reported the use of 4-bromo-2-methylbenzoic acid in NaBrO3-NaHSO3The yield of the method is not high and is 42% (Safdar, H.; Rahman, M.lqbalC.Ernst, B.; and improved method for the synthesis of gamma-lactic using Sodium borate and Sodium hydroxide Sulfite)](ii) a tetra.Lett.2001,42: 1647-1649); in 2002, Jiang national defense et al reported that 5-bromobenzofuranone was prepared from o-xylene as a raw material through bromination and catalytic oxidation, but the yield of 5-bromobenzofuranone was 69.1%, which is not high (Jiang national defense, Wegener. 5-bromobenzofuranone research on the synthetic method [, ]J]Journal of Hunan university, 2002,29(3): 12-15).
In conclusion, the existing method for preparing 5-bromobenzofuranone has the problem of low yield.
Disclosure of Invention
In view of the above, the invention provides a preparation method of 5-bromobenzofuranone. The method provided by the invention is simple to operate and high in yield.
In order to achieve the above object, the present invention provides the following technical solutions:
a preparation method of 5-bromobenzofuranone comprises the following steps:
mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone;
and mixing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the organic base and a second organic solvent, and carrying out cyclization reaction to obtain the 5-bromobenzofuranone.
Preferably, the brominating agent includes any one or more of hydrobromic acid, hypobromous acid, N-bromosuccinimide, octyl bromide, liquid bromine, 1, 3-dibromo-5, 5-dimethylhydantoin and benzyl ammonium tribromide.
Preferably, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the brominating agent is 1 (0.5-5).
Preferably, the catalyst comprises any one or more of an iron-based catalyst, a copper-based catalyst, a zinc-based catalyst and an aluminum-based catalyst;
the mass of the catalyst is 5-10% of that of the 2-hydroxy-5-bromoacetophenone.
Preferably, the temperature of the bromination reaction is 80-100 ℃ and the time is 10-15 h.
Preferably, the organic base comprises any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide and potassium ethoxide.
Preferably, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is 1 (0.5-3).
Preferably, the temperature of the cyclization reaction is 20-30 ℃ and the time is 4-8 h.
Preferably, the first organic solvent comprises any one or more of 1, 2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate.
Preferably, the second organic solvent includes any one of dichloromethane, toluene, benzene, chloroform and ethyl acetate.
The invention provides a preparation method of 5-bromobenzofuranone, which comprises the following steps: mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone; and mixing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the organic base and a second organic solvent, and carrying out cyclization reaction to obtain the 5-bromobenzofuranone. The method takes 2-hydroxy-5-bromoacetophenone as a raw material, and the 5-bromobenzofuran is prepared by carrying out bromination reaction and cyclization reaction in sequence. Experimental data of the embodiment of the invention show that the yield of the 5-bromobenzofuran is up to 83.7%, and the yield is high.
Furthermore, the raw materials and the catalyst required by the method are easier to obtain, the reaction time is short, and the operation is simpler.
Drawings
FIG. 1 is a diagram of 5-bromobenzofuranone prepared in example 11H-NMR chart.
Detailed Description
The invention provides a preparation method of 5-bromobenzofuranone, which comprises the following steps:
mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone;
and mixing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the organic base and a second organic solvent, and carrying out cyclization reaction to obtain the 5-bromobenzofuranone.
Unless otherwise specified, the starting materials for the preparation used in the present invention are commercially available.
In the invention, the synthetic route of the 5-bromobenzofuranone is shown as a formula 1:
the method comprises the steps of mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. In the present invention, the brominating agent preferably includes any one or more of hydrobromic acid, hypobromous acid, N-bromosuccinimide, octyl bromide, liquid bromine, 1, 3-dibromo-5, 5-dimethylhydantoin and benzyl ammonium tribromide, and more preferably liquid bromine, hydrobromic acid, N-bromosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin or octyl bromide. The molar ratio of the 2-hydroxy-5-bromoacetophenone to the bromization reagent is preferably 1 (0.5-5), more preferably 1 (0.5-3), even more preferably 1 (0.8-3), and most preferably 1 (1-2). In the present invention, the catalyst preferably includes any one or more of an iron-based catalyst, a copper-based catalyst, a zinc-based catalyst, and an aluminum-based catalyst. In the present invention, the iron-based catalyst preferably includes one or more of iron powder, iron tribromide and iron chloride, and more preferably includes iron powder and/or iron tribromide. The copper-based catalyst preferably comprises cuprous bromide and/or cupric bromide, more preferably cupric bromide. In the present invention, the zinc-based catalyst preferably includes zinc chloride, and the aluminum-based catalyst preferably includes aluminum chloride. In the invention, the mass of the catalyst is preferably 5-10%, more preferably 6-9%, even more preferably 6.5-8.5%, and most preferably 7-8.5% of the mass of the 2-hydroxy-5-bromoacetophenone. In the invention, the catalysts of the above types are relatively easy to obtain, and the catalytic activity is better, which is beneficial to reducing the complexity of a reaction system. In the present invention, the first organic solvent preferably includes any one or more of 1, 2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate. When the first organic solvent is preferably a mixed solvent of two solvents, the mixed solvent is preferably a mixed solvent of 1, 2-dichloroethane and ethyl acetate, a mixed solvent of dichloromethane and butyl acetate, a mixed solvent of 1, 2-dichloroethane and butyl acetate or a mixed solvent of trichloromethane and ethyl acetate, more preferably a mixed solvent of 1, 2-dichloroethane and ethyl acetate or a mixed solvent of trichloromethane and ethyl acetate, and when the mixed solvent is a mixed solvent of 1, 2-dichloroethane and ethyl acetate, the volume ratio of 1, 2-dichloroethane to ethyl acetate is preferably 1 (1-2), more preferably 1 (1-1.5), and more preferably 1: 1; when the mixed solvent is a mixed solvent of trichloromethane and ethyl acetate, the volume ratio of trichloromethane to ethyl acetate is preferably 1 (1-2), more preferably 1 (1-1.5), and even more preferably 1: 1. The invention preferably adopts a mixed solvent, so that the yield of the bromination reaction can be further improved.
In the invention, the mass-to-volume ratio of the 2-hydroxy-5-bromoacetophenone to the first organic solvent is preferably 1g (8-12) mL, more preferably 1g (9-11) mL, and even more preferably 1g (10-11) mL. In the invention, the bromination reaction is preferably carried out in a reaction kettle, the temperature of the bromination reaction is preferably 80-100 ℃, more preferably 80-95 ℃, further preferably 85-90 ℃, and the time of the bromination reaction is preferably 10-15 h, more preferably 12-15 h, further preferably 13-14 h. The bromination reaction is preferably carried out under stirring conditions in the present invention. The invention preferably adopts a gas phase monitoring mode to determine the progress of the bromination reaction, wherein the gas phase monitoring mode is a means well known by the person skilled in the art, and the gas phase monitoring is based on that the 2-hydroxy-5-bromoacetophenone in the reaction system can not be detected, so that the raw materials are completely reacted. In the invention, the yield of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is preferably improved by adjusting the proportion of the raw materials, the type and the amount of the catalyst and the type of the first organic solvent, so that a bromine atom can more easily react with a hydrogen atom on a ketone group on a benzene ring.
After 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained, the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, an organic base and a second organic solvent are mixed for cyclization reaction to obtain 5-bromobenzofuranone. In the invention, preferably, the mixture obtained after the bromination reaction is reduced to room temperature, then solid-liquid separation and rotary evaporation are sequentially carried out to obtain a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is re-dissolved by adding water to obtain a crude product solution, then, the crude product is easily subjected to second organic solvent extraction, water washing, drying and desiccant removal in sequence to obtain a second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, and then the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is mixed with an organic base for cyclization reaction. The second organic solvent is preferably used as an extraction phase of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, and the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is purified and simultaneously mixed with raw materials required by a cyclization reaction, so that the operation steps are simplified. In the present invention, the solid-liquid separation is preferably filtration. After the solid-liquid separation, the filtrate is taken and subjected to rotary evaporation, wherein the temperature of the rotary evaporation is preferably 30-42 ℃, more preferably 35-40 ℃, and further preferably 35-38 ℃. The present invention does not require any particular time for the rotary evaporation, and the solvent in the filtrate is evaporated to dryness. In the present invention, the second organic solvent preferably includes any one of dichloromethane, toluene, benzene, chloroform and ethyl acetate, and more preferably includes any one of dichloromethane, toluene and trichlorotoluene. In the present invention, the water washing is preferably performed with brine, preferably a chloride solution, preferably a sodium chloride solution. The concentration of the sodium chloride solution is not particularly required, and the effects of washing and obvious layering can be realized. In the present invention, the drying agent is preferably anhydrous sodium sulfate, and the manner of removing the drying agent is preferably filtration. The temperature of the second organic solvent solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is preferably reduced to 0-5 ℃, more preferably to 0 ℃, and then the second organic solvent solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is mixed with the organic base, and the temperature of the second organic solvent solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is preferably reduced to the temperature range, so that the intensity of the reaction is reduced by adding the base, the safety of the reaction is improved, the temperature of the reaction is conveniently controlled in a proper range, and the yield of the product is improved.
In the present invention, the organic base preferably includes any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide, and potassium ethoxide, and more preferably includes any one or more of triethylamine, pyridine, and sodium methoxide. In the invention, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is preferably 1 (0.5-3), more preferably 1 (0.5-2), even more preferably 1 (0.5-1.5), and most preferably 1 (0.7-1.0). In the invention, after the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone and the organic base are mixed, the temperature is preferably raised to the temperature of the cyclization reaction under the stirring condition for reaction. In the invention, the temperature of the cyclization reaction is preferably 20-30 ℃, more preferably 25-28 ℃, and the time is preferably 4-8 h, more preferably 5-7.5 h, and further preferably 6-7 h. The present invention preferably determines the progress of the cyclization reaction by means of gas phase monitoring, which is a means well known to those skilled in the art, based on no detection of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone in the reaction system, indicating that the starting material has reacted completely.
After the cyclization reaction is finished, the invention preferably carries out post-treatment on the system after the cyclization reaction to obtain the 5-bromobenzofuran. In the present invention, the post-treatment preferably comprises the steps of: and sequentially carrying out quenching, first washing, first separation and first rotary evaporation on the system after the cyclization reaction to obtain a crude product of 5-bromobenzofuran, and sequentially carrying out redissolution, second washing, second separation, second rotary evaporation, recrystallization, solid-liquid separation and drying on the crude product of 5-bromobenzofuran to obtain the 5-bromobenzofuran. In the invention, the system after the reaction is preferably quenched by water, the volume ratio of the water for quenching reaction to the reaction system is preferably (1-3): 1, more preferably (1.5-2.5): 1, in the invention, the first washing is preferably washed by brine, the brine is preferably sodium chloride solution, the concentration of the sodium chloride solution is preferably 1-2 mol/L, and the volume ratio of the brine to the water for quenching reaction is preferably 1 (0.5-1.8), more preferably 1 (0.75-1.5), more preferably 1 (0.75-1.0). According to the invention, an organic phase containing the crude product of the 5-bromobenzofuran is obtained through the first separation, and then the organic phase is subjected to first rotary evaporation to obtain the crude product of the 5-bromobenzofuran. The temperature of the first rotary evaporation is preferably 30-45 ℃, and more preferably 35-40 ℃. The temperature of the first rotary evaporation is not particularly required, and the organic phase is completely evaporated to dryness. In the invention, the solvent for redissolution is preferably ethyl acetate, the volume ratio of the ethyl acetate to the solution is preferably 2:1, the second washing is preferably brine, the brine is preferably sodium chloride solution, the concentration of the sodium chloride solution is preferably 1-2 mol/L, and the volume ratio of the brine to the solvent for redissolution is preferably (0.5-1): 1, and more preferably (0.5-0.8): 1. According to the invention, an organic phase containing the 5-bromobenzofuran is obtained through second separation, and then rotary evaporation is carried out on the organic phase. In the invention, the temperature of the second rotary evaporation is preferably 30-45 ℃, more preferably 35-40 ℃, and the volume of the organic phase after the second rotary evaporation is 20-30% of the volume before the second rotary evaporation, more preferably 25-30%.
In the present invention, the recrystallization mode is preferably that a recrystallization solvent is added to the system after the second rotary distillation, the recrystallization solvent is preferably petroleum ether, and the volume ratio of the amount of the petroleum ether to the system after the second rotary distillation is preferably 0.5: 1. In the invention, after adding a solvent for recrystallization into the system after the second rotary evaporation, the temperature is reduced to 4 ℃ for recrystallization. In the invention, the solid-liquid separation mode is filtration, and the filtration mode is preferably adopted to obtain the recrystallized 5-bromobenzofuran. According to the invention, the recrystallized 5-bromobenzofuran is pumped to obtain the 5-bromobenzofuran.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
Adding 10g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the mixture in a solvent consisting of 50mL of ethyl acetate and 50mL of 1, 2-dichloroethane, sequentially adding 7.43g of liquid bromine and 0.8g of copper bromide, heating the reaction kettle to 100 ℃, stirring and reacting for 12 hours, and monitoring the reaction progress by gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 40 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. Then 20mL of water is added into the crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, 60mL of dichloromethane is added for extraction, the dichloromethane phases are separated and obtained, the dichloromethane phase is washed by 60mL of brine, then the dichloromethane phase is dried by 6g of anhydrous sodium sulfate, and the drying agent is removed by filtration to obtain a dichloromethane solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, and the solution is directly used for the next reaction.
Cooling a dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to 0 ℃, dropwise adding 4.7g of triethylamine, heating a reaction system to 25 ℃, stirring for reacting for 6 hours, and monitoring the reaction process by using a gas phase. After the reaction, 30mL of water was added to the reaction system to quench, 40mL of brine was added to wash the reaction system, and after the washing was completed, the dichloromethane phase and the aqueous phase were separated. The dichloromethane phase is rotary evaporated at 40 ℃ until the solvent is completely rotary evaporated to obtain the crude product of 5-bromobenzofuranone. Re-dissolving the crude product with 80mL of ethyl acetate, washing with 40mL of brine, separating an organic phase from a water phase, carrying out rotary evaporation and concentration on the organic phase at 40 ℃ to 25% of the original volume, adding 20mL of petroleum ether into the rotary evaporated solution for recrystallization, filtering and collecting a solid, and pumping the solid by using an oil pump to obtain a pure 5-bromobenzofuranone product. The yield of 5-bromobenzofuranone was calculated and determined to be 83.6% with a purity of 99.4%. FIG. 1 shows the preparation of 5-bromobenzofuranone prepared in example 11H-NMR chart. As can be seen from FIG. 1, the characteristic peaks of 5-bromobenzofuranone are clear, indicating that 5-bromobenzofuranone prepared by the preparation method of example 1 has high purity.
Example 2
Adding 20g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the mixture in a solvent consisting of 100mL of ethyl acetate and 100mL of trichloromethane, sequentially adding 14.86g of hydrobromic acid and 1.5g of iron powder, heating the reaction kettle to 80 ℃, stirring and reacting for 15 hours, and monitoring the reaction process by gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 35 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. And then adding 40mL of water into the crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, adding 120mL of trichloromethane to extract the crude product, layering the obtained product to obtain a trichloromethane phase, washing the trichloromethane phase with 120mL of saline, drying the trichloromethane phase with 12g of anhydrous sodium sulfate, and filtering the obtained product to remove a drying agent to obtain a trichloromethane solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, wherein the solution is directly used for the next reaction.
Cooling the trichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to 0 ℃, dropwise adding 9.4g of pyridine, heating the reaction system to 20 ℃, stirring for reacting for 8 hours, and monitoring the reaction process by gas phase. After the reaction, 60mL of water is added into the reaction system for quenching, 80mL of brine is added for washing, and after the washing is finished, the chloroform phase is separated from the water phase. And (3) carrying out rotary evaporation on the chloroform phase at 35 ℃ until the solvent is completely subjected to rotary evaporation to obtain a crude product of 5-bromobenzofuranone. Redissolving the crude product by 160mL of ethyl acetate, washing by 80mL of brine, separating an organic phase from a water phase, carrying out rotary evaporation and concentration on the organic phase at 35 ℃ to 20% of the original volume, adding 40mL of petroleum ether into the rotary evaporated solution for recrystallization, filtering and collecting a solid, and pumping the solid by an oil pump to obtain a pure 5-bromobenzofuranone product. The yield of 5-bromobenzofuranone was calculated and determined to be 82.7% with a purity of 99.1%.
Example 3
Adding 30g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the mixture in a solvent consisting of 150mL of butyl acetate and 150mL of dichloromethane, sequentially adding 22.3g N-bromosuccinimide and 2.5g of ferric tribromide, heating the reaction kettle to 85 ℃, stirring and reacting for 13 hours, and monitoring the reaction process in a gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 40 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. Then 60mL of water is added into the crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, 180mL of toluene is added for extraction, the layers are separated to obtain a toluene phase, the toluene phase is washed with 180mL of brine, then the toluene phase is dried with 18g of anhydrous sodium sulfate, and the drying agent is removed by filtration to obtain a toluene solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which is directly used for the next reaction.
Cooling the toluene solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to 0 ℃, dropwise adding 14.2g of sodium methoxide, heating the reaction system to 26 ℃, stirring for reaction for 7h, and monitoring the reaction process by gas phase. After the reaction, 180mL of water was added to the reaction system to quench, 120mL of brine was added to wash, and after washing, the toluene phase was separated from the aqueous phase. And (3) carrying out rotary evaporation on the toluene phase at 40 ℃ until the solvent is completely distilled, so as to obtain a crude product of 5-bromobenzofuranone. Redissolving the crude product by using 240mL of ethyl acetate, washing by using 120mL of brine, separating an organic phase from a water phase, carrying out rotary evaporation and concentration on the organic phase at 40 ℃ to 30% of the original volume, adding 60mL of petroleum ether into the rotary evaporated solution for recrystallization, then filtering and collecting a solid, and pumping the solid by using an oil pump to obtain a pure 5-bromobenzofuranone product. The yield of 5-bromobenzofuranone was calculated and determined to be 83.1% with a purity of 98.6%.
Example 4
Adding 40g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the mixture in a solvent consisting of 200mL of butyl acetate and 200mL of dichloroethane, sequentially adding 29.7g of 1, 3-dibromo-5, 5-dimethylhydantoin and 3g of zinc chloride, heating the reaction kettle to 90 ℃, stirring and reacting for 13 hours, and monitoring the reaction process in a gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 38 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. Then 80mL of water is added into the crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, 240mL of ethyl acetate is added for extraction, and layers are separated to obtain an ethyl acetate phase, the ethyl acetate phase is washed with 240mL of brine, then the toluene phase is dried with 25g of anhydrous sodium sulfate, and the drying agent is removed by filtration to obtain an ethyl acetate solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which is directly used for the next reaction.
Cooling the ethyl acetate solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to 0 ℃, dropwise adding 19g of sodium ethoxide, heating the reaction system to 28 ℃, stirring for reacting for 5h, and monitoring the reaction process by gas phase. After the reaction, 120mL of water was added to the reaction system to quench, 160mL of brine was added to wash, and after the washing, the ethyl acetate phase was separated from the aqueous phase. And carrying out rotary evaporation on the ethyl acetate phase at 38 ℃ until the solvent is completely subjected to rotary evaporation to obtain a crude product of the 5-bromobenzofuranone. Redissolving the crude product by using 320mL of ethyl acetate, washing by using 160mL of brine, separating an organic phase from a water phase, carrying out rotary evaporation concentration on the organic phase at 40 ℃ to 25% of the original volume, then adding 80mL of petroleum ether into the solution after the rotary evaporation for recrystallization, then filtering and collecting a solid, and pumping the solid by using an oil pump to obtain a pure product of the 5-bromobenzofuranone. The yield of 5-bromobenzofuranone was calculated and determined to be 82.1% with a purity of 98.2%.
Example 5
Adding 50g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the 2-bromoacetophenone in 500mL of 1, 2-dichloroethane, sequentially adding 37g of bromooctane and 4g of aluminum chloride, heating the reaction kettle to 95 ℃, stirring and reacting for 12 hours, and monitoring the reaction process in a gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 40 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. And then adding 100mL of water into the crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, adding 300mL of trichloromethane to extract the crude product, carrying out layering to obtain a trichloromethane phase, washing the trichloromethane phase with 300mL of saline, drying the trichloromethane phase with 30g of anhydrous sodium sulfate, and filtering to remove a drying agent to obtain a trichloromethane solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, wherein the solution is directly used for the next reaction.
Cooling a trichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to 0 ℃, dropwise adding 14g of potassium ethoxide, heating a reaction system to 25 ℃, stirring for reaction for 7 hours, and monitoring the reaction process by using a gas phase. After the reaction is finished, adding 150mL of water into the reaction system for quenching, adding 200mL of brine for washing, and separating the chloroform phase from the water phase after the washing is finished. And (3) carrying out rotary evaporation on the chloroform phase at 40 ℃ until the solvent is completely subjected to rotary evaporation to obtain a crude product of 5-bromobenzofuranone. Re-dissolving the crude product with 400mL of ethyl acetate, washing with 200mL of brine, separating an organic phase from a water phase, carrying out rotary evaporation and concentration on the organic phase at 40 ℃ to 20% of the original volume, adding 100mL of petroleum ether into the rotary evaporated solution for recrystallization, filtering and collecting a solid, and pumping the solid by using an oil pump to obtain a pure 5-bromobenzofuranone product. The yield of 5-bromobenzofuranone was 82.7% and the purity 98.3% was calculated and determined.
Example 6
Adding 100g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the 2-bromoacetophenone in a solvent consisting of 500mL of ethyl acetate and 500mL of 1, 2-dichloroethane, sequentially adding 74.3g of liquid bromine and 8g of copper bromide, heating the reaction kettle to 100 ℃, stirring and reacting for 10 hours, and monitoring the reaction process by using a gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 40 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. Then adding 200mL of water into the crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, adding 600mL of dichloromethane for extraction, separating layers to obtain a dichloromethane phase, washing the dichloromethane phase with 600mL of brine, drying the dichloromethane phase with 60g of anhydrous sodium sulfate, and filtering to remove a drying agent to obtain a dichloromethane solution containing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, wherein the dichloromethane solution is directly used for the next reaction.
Cooling a dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to 0 ℃, dropwise adding 47.1g of triethylamine, heating a reaction system to 25 ℃, stirring for reacting for 6 hours, and monitoring the reaction process by using a gas phase. After the reaction, 300mL of water was added to the reaction system to quench, 400mL of brine was added to wash the reaction system, and after the washing was completed, the methylene chloride phase and the aqueous phase were separated. The dichloromethane phase is rotary evaporated at 40 ℃ until the solvent is completely rotary evaporated to obtain the crude product of 5-bromobenzofuranone. Re-dissolving the crude product with 800mL of ethyl acetate, washing with 400mL of brine, separating an organic phase from a water phase, carrying out rotary evaporation and concentration on the organic phase at 40 ℃ to 25% of the original volume, adding 200mL of petroleum ether into the rotary evaporated solution for recrystallization, filtering and collecting a solid, and pumping the solid by using an oil pump to obtain a pure 5-bromobenzofuranone product. The yield of 5-bromobenzofuranone was calculated and determined to be 83.7% with a purity of 99.3%.
Example 7
Adding 1000g of 2-hydroxy-5-bromoacetophenone into a reaction kettle, dissolving the mixture in a solvent consisting of 5000mL of ethyl acetate and 5000mL of 1, 2-dichloroethane, sequentially adding 743g of liquid bromine and 80g of copper bromide, heating the reaction kettle to 100 ℃, stirring and reacting for 10 hours, and monitoring the reaction process by gas phase. After the reaction is finished, cooling the reaction kettle to room temperature, filtering to remove solid impurities in the reaction system to obtain filtrate, and performing rotary evaporation on the filtrate at 40 ℃ until the solvent is evaporated to dryness to obtain a crude product of the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. Then 2000mL of water was added to the crude 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve it, 6000mL of dichloromethane was added for extraction, the layers were separated to give a dichloromethane phase, the dichloromethane phase was washed with 6000mL of brine, then the dichloromethane phase was dried over 600g of anhydrous sodium sulfate, and the drying agent was removed by filtration to give a dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which was used directly in the next reaction.
The dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone was cooled to 0 ℃, 471g of triethylamine was added dropwise, the reaction system was heated to 25 ℃, stirred and reacted for 6h, and the reaction progress was monitored in the gas phase. After the reaction, 3000mL of water was added to the reaction system to quench, 4000mL of brine was added to wash, and after the washing, the dichloromethane phase was separated from the aqueous phase. The dichloromethane phase is rotary evaporated at 40 ℃ until the solvent is completely rotary evaporated to obtain the crude product of 5-bromobenzofuranone. Redissolving the crude product by 8000mL ethyl acetate, washing by 4000mL saline, separating an organic phase and a water phase, carrying out rotary evaporation concentration on the organic phase at 40 ℃ to 25% of the original volume, adding 2000mL petroleum ether into the rotary evaporated solution for recrystallization, filtering and collecting a solid, and pumping the solid by an oil pump to obtain a pure 5-bromobenzofuranone product. The yield of 5-bromobenzofuranone was calculated and determined to be 83.5% with a purity of 99.5%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of 5-bromobenzofuranone is characterized by comprising the following steps:
mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone;
and mixing the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the organic base and a second organic solvent, and carrying out cyclization reaction to obtain the 5-bromobenzofuranone.
2. The method according to claim 1, wherein the brominating agent includes any one or more of hydrobromic acid, hypobromous acid, N-bromosuccinimide, octyl bromide, liquid bromine, 1, 3-dibromo-5, 5-dimethylhydantoin and benzyl ammonium tribromide.
3. The preparation method according to claim 1 or 2, characterized in that the molar ratio of the 2-hydroxy-5-bromoacetophenone to the brominating agent is 1 (0.5-5).
4. The production method according to claim 1, wherein the catalyst comprises any one or more of an iron-based catalyst, a copper-based catalyst, a zinc-based catalyst, and an aluminum-based catalyst;
the mass of the catalyst is 5-10% of that of the 2-hydroxy-5-bromoacetophenone.
5. The preparation method according to claim 1, wherein the temperature of the bromination reaction is 80-100 ℃ and the time is 10-15 h.
6. The method according to claim 1, wherein the organic base comprises any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide, and potassium ethoxide.
7. The preparation method according to claim 1 or 6, characterized in that the molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is 1 (0.5-3).
8. The method according to claim 1, wherein the cyclization reaction is carried out at a temperature of 20 to 30 ℃ for 4 to 8 hours.
9. The method of claim 1, wherein the first organic solvent comprises any one or more of 1, 2-dichloroethane, chloroform, dichloromethane, ethyl acetate, and butyl acetate.
10. The method according to claim 1, wherein the second organic solvent comprises any one of dichloromethane, toluene, benzene, chloroform, and ethyl acetate.
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