CN103724304A - Preparation method of 5-bromobenzofuran - Google Patents
Preparation method of 5-bromobenzofuran Download PDFInfo
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- CN103724304A CN103724304A CN201310720714.5A CN201310720714A CN103724304A CN 103724304 A CN103724304 A CN 103724304A CN 201310720714 A CN201310720714 A CN 201310720714A CN 103724304 A CN103724304 A CN 103724304A
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- cumarone
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- 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
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 5-bromobenzofuran. The preparation method of 5-bromobenzofuran comprises the following steps: p-bromophenol and 2-bromoacetaldehyde dimethyl acetal or 2-chloroacetaldehyde dimethyl acetal react for several hours at a proper temperature in the presence of proper solvent and alkali to generate 1-bromo-4'-(2,2-dimethoxyethyl) benzene; the 1-bromo-4'-(2,2-dimethoxyethyl) benzene is heated in the corresponding solvent in the presence of acid, and experiences a cyclization reaction; the product is purified to obtain 5-bromobenzofuran. The method provided by the invention has the beneficial effects that 5-bromobenzofuran is prepared by a two-step process in the reaction, the operation is simple and convenient, the production cost is reduced, and industrial large-scale production is easy to realize; meanwhile, environmental pollution caused by a heavy metal catalyst is avoided.
Description
Technical field
The invention belongs to organic synthesis field, particularly a kind of preparation method of 5-bromine cumarone.
Background technology
Cumarone and derivative thereof are very important organic compound, have very high biological activity and are extensively present among many natural product skeletons, and therefore synthetic having obtained of cumarone and derivative thereof paid close attention to widely.Had a lot of bibliographical informations synthesizing of cumarone ring, the synthetic of classical cumarone is, by Mono Chloro Acetic Acid, O-alkylation is occurred salicylic aldehyde to, and then dehydration obtains.In recent years there is O-alkylation in useful phenol and its derivatives and monochloroacetaldehyde or bromoacetaldehyde also, and then under sour effect, dehydration obtains.
Benzofuran compounds has the multiple biological activitys such as Kang Group amine, antitumor and anti-arrhythmia, and wherein a lot of active compounds are expected to become the medicine for the treatment of relative disease.Benzofuran derivative occupies very important position in pharmaceutical chemistry, in all many-sides such as sterilization, anticancer, antiviral, immunosuppressor, anti-oxidant and Green Tea Extracts, demonstrates good biological activity and pharmaceutical use.Wherein, the chemicals that 5-alpha reductase inhibitor that is used for the treatment of the A1 glycosides receptor antagonist of cardiovascular disease and is used for the treatment of hyperplasia of prostate etc. has cumarone ring system structure has been applied to clinical.Along with further investigation and the widespread use of people to this heterocyclic compounds, the benzofuran derivative of finding and screen the pharmacologically active with novel chemical structure and high-efficiency low-toxicity day by day receives people's concern in the synthetic research field of medicine.The prevention that for example L-3428 sheet quivers for life-threatening paroxysm ventricular tachycardia and chamber, also can be used for paroxysmal supraventricular tachycardia, paroxysm auricular flutter, atrial fibrillation that other drug is invalid, comprise the treatment that maintains after merging preexcitation syndrome person and lasting atrial fibrillation, auricular flutter electrical conversion, can be used for continuing the control of atrial fibrillation, Pu Shi chamber, room rate.
No matter be at present external or the method for domestic synthetic benzofuran compounds mainly contains that traditional method, palladium catalyze and synthesize, copper catalyzes and synthesizes and other precious metal catalyst is synthetic.Traditional method has playing an important role of biological activity cumarone synthetic, but ubiquity route is long, and substrate and reaction conditions require harsh, replaces functional group and expands limited problem.Palladium and other precious metal synthesize cumarone and can overcome the shortcoming of prior synthesizing method as catalyzer, productive rate has had further raising, but cost is higher.In recent years, cheap transition metal copper has just become the new focus of people's researchs gradually, has had more gratifying achievement with copper as the research of the synthetic cumarone of catalyzer, still still has the shortcomings such as substrate reagents ratio restricted, used is more expensive.Although these achievements are extremely successful, but its suitability for industrialized production has run into great challenge, and the heavy metal catalyst using will will pollute environment.
Summary of the invention
The present invention is in order to make up the defect of prior art, and a kind of preparation method that can be applied to laboratory and the synthetic 5-bromine cumarone of industrialization is provided.
The present invention is achieved through the following technical solutions:
A preparation method for 5-bromine cumarone, is characterized in that, comprises the following steps:
(1) in solvent, adopting p bromophenol and 2-bromoacetaldehyde dimethyl acetal or 2-monochloroacetaldehyde dimethyl acetal is reactant, under the effect of alkali, in 25 ~ 153 ℃ of reactions, within 1 ~ 36 hour, generates bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of 1-;
(2), in solvent, bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of 1-is heated to 40 ~ 210 ℃ and generates 5-bromine cumarone through cyclisation under sour effect, obtains 5-bromine cumarone after purification.
In described step (1), reactant is p bromophenol and 2-bromoacetaldehyde dimethyl acetal, and charging capacity is p bromophenol: 2-bromoacetaldehyde dimethyl acetal=1:1.5 ~ 2 are more than mol ratio.
In described step (1), solvent is tetrahydrofuran (THF), dioxane, acetonitrile, N, N-dimethylformamide, N, any one material in N-dimethyl acetyl ammonia (DMA) or N-Methyl pyrrolidone (NMP), solvent load is p bromophenol: solvent=1:4 ~ 4.6 are more than weight ratio.
In described step (1), alkali is saleratus, salt of wormwood, and sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium hydroxide, any one material in potassium hydroxide or sodium hydride, charging capacity is p bromophenol: alkali=4:1 ~ 1.3 are more than mol ratio.
In described step (2), solvent is benzene, toluene, and chlorobenzene, any one material in dimethylbenzene or oil of mirbane, solvent load is bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of 1-: solvent=1:4 ~ 4.2 are more than weight ratio.
In described step (2), acid is sulfuric acid, any one material in phosphoric acid or polyphosphoric acid, and charging capacity is bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of 1-: acid=1:5 ~ 5.5 are more than mol ratio.
Described reaction conditions adopts the one in following scheme: at 25 ~ 50 ℃, react cyclisation after 1 ~ 5 hour and be heated to 40 ~ 80 ℃, at 50 ~ 80 ℃, react cyclisation after 5 ~ 8 hours and be heated to 80 ~ 120 ℃, react after 8 ~ 12 hours cyclisation at 80 ~ 120 ℃ and be heated to react cyclisation after 12 ~ 18 hours at 120 ~ 140 ℃ or 120 ~ 153 ℃ and be heated to 140 ~ 180 ℃.
In described step (2), 5-bromine cumarone method of purification refers to separatory, filter, and water washing, anhydrous sodium sulfate drying, evaporation concentration, 140 ℃ ~ 150 ℃ cuts, rectifying are got in distillation.
The invention has the beneficial effects as follows: reaction of the present invention adopts two-step approach to prepare 5-bromine cumarone, easy and simple to handle, has reduced production cost, be easy to industrialization and amplify, avoided again simultaneously heavy metal catalyst by environment by the pollution causing.
Embodiment
Embodiment 1:
Adding 1 in flask at the bottom of one 2000 mL San Kou gardens, 4-dioxane (800 mL), then adds p bromophenol (210 g, 1.213 mol), salt of wormwood (750 g successively, 5.426 mol) and 2-bromoacetaldehyde dimethyl acetal (300 g, 1.775 mol).Start stirring reflux 24 hours.TLC and GC follow the tracks of reaction.After having reacted, most of Isosorbide-5-Nitrae-dioxane is removed in distillation.In resistates, add water and each 600 mL of ethyl acetate, be uniformly mixed liquid 30 minutes, separate organic phase.Water, again with 200 mL ethyl acetate extractions, merges after organic phase, spends the night by dried over sodium sulfate.(340 g) are directly used in next step reaction to the thick product of gained.
In flask at the bottom of one 5000 mL San Kou gardens, add chlorobenzene (1200 mL), (340 g), and (850 g) for phosphoric acid then to add successively bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of above-mentioned thick product 1-.Start stirring reflux 24 hours.TLC and GC follow the tracks of reaction.After having reacted, reaction solution is chilled to after room temperature, lower floor is separated.Organic phase water (600 mL) and sodium hydroxide (2 mol/L, 500 mL) washing.Dried over sodium sulfate is spent the night.Most of chlorobenzene is removed in distillation.Then changing underpressure distillation into obtains thick product 5-bromine cumarone (205 g).After rectifying, obtain sterling 5-bromine cumarone 149 g, productive rate 62.3%.
Embodiment 2:
Adding N in flask at the bottom of one 2000 mL San Kou gardens, dinethylformamide (800 mL), then adds p bromophenol (210 g, 1.213 mol), salt of wormwood (750 g successively, 5.426 mol) and 2-bromoacetaldehyde dimethyl acetal (300 g, 1.775 mol).Start stirring reflux 20 hours.TLC and GC follow the tracks of reaction.After having reacted, most of DMF is removed in distillation.In resistates, add water and each 800 mL of ethyl acetate, be uniformly mixed liquid 60 minutes, separate organic phase.Water is used 300 mL ethyl acetate extracting twice again, merges after organic phase, and water (300 mL) washing organic phase twice, spends the night by dried over sodium sulfate.(350 g), is directly used in next step reaction for the thick product of gained.
In flask at the bottom of one 5000 mL San Kou gardens, add chlorobenzene (1200 mL), (350 g), and (870 g) for phosphoric acid then to add successively bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of above-mentioned thick product 1-.Start stirring reflux 28 hours.TLC and GC follow the tracks of reaction.After having reacted, reaction solution is chilled to after room temperature, lower floor is separated.Organic phase water (600 mL) and sodium hydroxide (2mol/L, 600 mL) washing.Dried over sodium sulfate is spent the night.Most of chlorobenzene is removed in distillation.Then changing underpressure distillation into obtains thick product 5-bromine cumarone (245 g).After rectifying, obtain sterling 5-bromine cumarone 179 g, productive rate 74.9%.
Embodiment 3:
Adding N in flask at the bottom of one 2000 mL San Kou gardens, dinethylformamide (800 mL), then adds p bromophenol (210 g, 1.213 mol), salt of wormwood (750 g successively, 5.426 mol) and 2-monochloroacetaldehyde dimethyl acetal (222 g, 1.78 mol).Start stirring reflux 28 hours.TLC and GC follow the tracks of reaction.After having reacted, most of DMF is removed in distillation.In resistates, add water and each 800 mL of ethyl acetate, be uniformly mixed liquid 45 minutes, separate organic phase.Water is used 300 mL ethyl acetate extracting twice again, merges after organic phase, and water (300 mL) washing organic phase twice, spends the night by dried over sodium sulfate.(290 g), is directly used in next step reaction for the thick product of gained.
In flask at the bottom of one 5000 mL San Kou gardens, add chlorobenzene (1000 mL), then add successively chloro-4 '-(2, the 2-dimethoxy-ethyl) benzene (290g) of above-mentioned thick product 1-, (790 g) for phosphoric acid.Start stirring reflux 30 hours.TLC and GC follow the tracks of reaction.After having reacted, reaction solution is chilled to after room temperature, lower floor is separated.Organic phase water (500 mL) and sodium hydroxide (2mol/L, 500 mL) washing.Dried over sodium sulfate is spent the night.Most of chlorobenzene is removed in distillation.Then changing underpressure distillation into obtains thick product 5-bromine cumarone (215 g).After rectifying, obtain sterling 5-bromine cumarone 151 g, productive rate 63.2%.
Embodiment 4:
In flask at the bottom of one 2000 mL San Kou gardens, add tetrahydrofuran (THF) (800 mL), then add successively p bromophenol (210 g, 1.213 mol), salt of wormwood (750 g, 5.426 mol) and 2-bromoacetaldehyde dimethyl acetal (300 g, 1.775 mol).Start stirring reflux 24 hours.TLC and GC follow the tracks of reaction.After having reacted, most of tetrahydrofuran (THF) is removed in distillation.In resistates, add water and each 600 mL of ethyl acetate, be uniformly mixed liquid 30 minutes, separate organic phase.Water, again with 200 mL ethyl acetate extractions, merges after organic phase, spends the night by dried over sodium sulfate.(270 g) are directly used in next step reaction to the thick product of gained.
In flask at the bottom of one 5000 mL San Kou gardens, add dimethylbenzene (1000 mL), (270 g), and (650 g) for polyphosphoric acid then to add successively bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of above-mentioned thick product 1-.Start and stir and reflux hours 18.TLC and GC follow the tracks of reaction.After having reacted, reaction solution is chilled to after room temperature, lower floor is separated.Organic phase water (500 mL) and sodium hydroxide (2mol/L, 400 mL) washing.Dried over sodium sulfate is spent the night.Most of dimethylbenzene is removed in distillation.Then changing underpressure distillation into obtains thick product 5-bromine cumarone (110 g).(78 g), productive rate 32.6% after rectifying, to obtain sterling 5-bromine cumarone.
Embodiment 5:
In the reactor of one 50 L, add DMF (21 L), then add successively p bromophenol (6.3 kg), add salt of wormwood (5.75 kg) and 2-bromoacetaldehyde dimethyl acetal (9 kg) in batches.Start stirring reflux 29 hours.TLC and GC follow the tracks of reaction.After having reacted, most of DMF is removed in distillation.In resistates, add water and each 12 L of ethyl acetate, be uniformly mixed liquid two hours, separate water and organic phase.Water is used 6 L ethyl acetate extracting twice again, merges after organic phase, and water (6 L) washing organic phase twice, spends the night by dried over sodium sulfate.The thick product of gained (10.2 kg), is directly used in next step reaction.
In the reactor of one 50 L, add chlorobenzene (20 L), then add successively bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene (5.1 kg) of above-mentioned thick product 1-, phosphoric acid (12 kg).Start stirring reflux 22 hours.TLC and GC follow the tracks of reaction.After having reacted, reaction solution is chilled to after room temperature, lower floor is separated.Organic phase water (8L) and sodium hydroxide (2mol/L, 8 L) washing.Dried over sodium sulfate is spent the night.Most of chlorobenzene is removed in distillation.Then change underpressure distillation into and obtain thick product 5-bromine cumarone (2.9 kg).After rectifying, obtain sterling 5-bromine cumarone 1.9 kg, productive rate 53%.Nuclear magnetic resonance spectroscopy,
1hNMR (DMSO-
d6) 600MHz:8.084ppm (s, 1H); 7.893ppm (s, 1H); 7.618ppm (d, J=1.4Hz, 1H); 7.480ppm (d, J=1.4Mz, 1H); 6.981ppm (s, 1H).Purity: 99% (GC).
Claims (8)
1. a preparation method for 5-bromine cumarone, is characterized in that, comprises the following steps:
(1) in solvent, adopting p bromophenol and 2-bromoacetaldehyde dimethyl acetal or 2-monochloroacetaldehyde dimethyl acetal is reactant, under the effect of alkali, in 25 ~ 153 ℃ of reactions, within 1 ~ 36 hour, generates bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of 1-;
(2), in solvent, bromo-4 '-(2, the 2-dimethoxy-ethyl) benzene of 1-is heated to 40 ~ 210 ℃ and generates 5-bromine cumarone through cyclisation under sour effect, obtains 5-bromine cumarone after purification.
2. the preparation method of 5-bromine cumarone according to claim 1, it is characterized in that: in described step (1), reactant is p bromophenol and 2-bromoacetaldehyde dimethyl acetal, and charging capacity is p bromophenol: 2-bromoacetaldehyde dimethyl acetal=1:1.5 ~ 2 are more than mol ratio.
3. the preparation method of 5-bromine cumarone according to claim 1, it is characterized in that: in described step (1), solvent is tetrahydrofuran (THF), dioxane, acetonitrile, N, N-dimethylformamide, N, any one material in N-dimethyl acetyl ammonia (DMA) or N-Methyl pyrrolidone (NMP), solvent load is p bromophenol: solvent=1:4 ~ 4.6 are more than weight ratio.
4. the preparation method of 5-bromine cumarone according to claim 1, it is characterized in that: in described step (1), alkali is saleratus, salt of wormwood, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium hydroxide, any one material in potassium hydroxide or sodium hydride, charging capacity is p bromophenol: alkali=4:1 ~ 1.3 are more than mol ratio.
5. the preparation method of 5-bromine cumarone according to claim 1, it is characterized in that: in described step (2), solvent is benzene, toluene, chlorobenzene, any one material in dimethylbenzene or oil of mirbane, solvent load is 1-bromo-4 '-(2,2-dimethoxy-ethyl) benzene: solvent=1:4 ~ 4.2 are more than weight ratio.
6. the preparation method of 5-bromine cumarone according to claim 1, it is characterized in that: in described step (2), acid is sulfuric acid, any one material in phosphoric acid or polyphosphoric acid, charging capacity is 1-bromo-4 '-(2,2-dimethoxy-ethyl) benzene: acid=1:5 ~ 5.5 are more than mol ratio.
7. the preparation method of 5-bromine cumarone according to claim 1, it is characterized in that: described reaction conditions adopts the one in following scheme: at 25 ~ 50 ℃, react cyclisation after 1 ~ 5 hour and be heated to 40 ~ 80 ℃, at 50 ~ 80 ℃, react cyclisation after 5 ~ 8 hours and be heated to 80 ~ 120 ℃, react after 8 ~ 12 hours cyclisation at 80 ~ 120 ℃ and be heated to react cyclisation after 12 ~ 18 hours at 120 ~ 140 ℃ or 120 ~ 153 ℃ and be heated to 140 ~ 180 ℃.
8. the preparation method of 5-bromine cumarone according to claim 1, is characterized in that: in described step (2), 5-bromine cumarone method of purification refers to separatory, filter water washing, anhydrous sodium sulfate drying, evaporation concentration, 140 ℃ ~ 150 ℃ cuts, rectifying are got in distillation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151151A (en) * | 2014-07-30 | 2014-11-19 | 天泽恩源（天津）医药技术有限公司 | Novel synthesis method of treprostinil |
Citations (1)
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| CN1720240A (en) * | 2002-10-09 | 2006-01-11 | 先灵公司 | Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1720240A (en) * | 2002-10-09 | 2006-01-11 | 先灵公司 | Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands |
Non-Patent Citations (1)
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| 黄志雄 等.: "1,2,6,7-四氢-8H-茚并[5,4-b]呋喃-8-酮的合成新方法", 《有机化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151151A (en) * | 2014-07-30 | 2014-11-19 | 天泽恩源（天津）医药技术有限公司 | Novel synthesis method of treprostinil |
| CN104151151B (en) * | 2014-07-30 | 2016-01-20 | 天泽恩源（天津）制药有限公司 | A kind of synthetic method of treprostinil you (Treprostinil) |
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Address after: 274100 Shandong city of Heze province Dingtao County Economic Development Zone, Fang Shan (Tianyuan West) Patentee after: Shandong You Bang biochemical technology company limited Address before: 274100 Shandong city of Heze province Dingtao County Economic Development Zone, Fang Shan (Tianyuan West) Patentee before: Dingyao County You Bang Chemical Co., Ltd. |