CN103755540A - Synthesis method of 2-chloro-3'-bromoacetophenone - Google Patents
Synthesis method of 2-chloro-3'-bromoacetophenone Download PDFInfo
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- CN103755540A CN103755540A CN201310699278.8A CN201310699278A CN103755540A CN 103755540 A CN103755540 A CN 103755540A CN 201310699278 A CN201310699278 A CN 201310699278A CN 103755540 A CN103755540 A CN 103755540A
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- bromoacetophenone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
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- 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 a synthesis method of 2-chloro-3'-bromoacetophenone (alpha-chloro-m-bromoacetophenone). The method is characterized by: taking m-aminoacetophenone as a raw material, subjecting the raw material to diazotization reaction to generate m-acetophenone diazo hydrobromide, carrying out Sandmeyer reaction to generate m-bromoacetophenone, and performing alpha-chlorination reaction to generate 2-chloro-3'-bromoacetophenone. The synthetic process route is simple, the conditions are mild, and the total yield is up to over 85%.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate to the methodology of organic synthesis of the chloro-3 '-bromoacetophenone of 2-.
Background technology
The chloro-3 '-bromoacetophenone of 2-is important organic raw material, can be for the synthesis of medical material and other organic compound.Bromoacetophenone between being generated by methyl phenyl ketone, can adopt methyl phenyl ketone in carbon tetrachloride solvent, at ferric bromide, as under catalyzer, generate, but this reaction generates ortho position and para-brominated methyl phenyl ketone simultaneously with bromine generation substitution reaction.The separation of reaction mixture, adopts rectification under vacuum method conventionally, and its separating effect is bad, be difficult to obtain content reach 99% between bromoacetophenone.Adopt alchlor catalyzer, in acetic acid or bromobenzene solvent, bromobenzene and acetyl bromide generation Friedel-Crafts reaction, can only generate parabromoacetophenone.Between position the synthetic of halo acetophenone be the long-term technical barrier of organic synthesis, also directly restricting the development of this series products and derivative thereof.The present invention is using m-aminophenyl ethyl ketone as starting point raw material, through diazotization and Sang Demai reaction, synthetic between bromine (chlorine) methyl phenyl ketone, have that chemo-selective is good, quality and a yield high, there is the using value of industrialization.Between the alpha-halogen of bromoacetophenone be also more difficult reaction because the easy polymerization of the product of alpha-halogen, and directly adopt bromine or chlorine to obtain, be not easy again to carry out.Adopt N-chlorosuccinimide (NCS), or N-bromo-succinimide (NBS) is as halo agent, under catalyzer and organic solvent effect, completes halogenating reaction, can obtain bromoacetophenone or m chloroacetophenone between high-content.Summary of the invention
The object of the present invention is to provide a kind of method of the synthetic chloro-3 '-bromoacetophenone of 2-: take m-aminophenyl ethyl ketone as raw material, through diazotization reaction, methyl phenyl ketone diazonium hydrobromate between generation; Through sandmeyer reaction, bromoacetophenone between generation; Through alpha-chloro reaction, generate the chloro-3 '-bromoacetophenone of 2-.
The present invention realizes by following method:
1, prepare certain density Hydrogen bromide, add m-aminophenyl ethyl ketone, under agitation, be cooled to 0～10 ℃ with icy salt solution, obtain the m-aminophenyl ethyl ketone hydrobromate aqueous solution standby.In addition, preparation sodium nitrite in aqueous solution, and from liquid level, be added drop-wise in above-mentioned solution.Keep 0～10 ℃ of temperature of reaction, after dropwising, continue insulation reaction more than 30 minutes, obtain a methyl phenyl ketone diazonium salt solution.
2, the diazonium salt solution of above-mentioned system is poured in the cold CuBr hydrobromic acid solution preparing, be heated to 30～65 ℃, fully stir and place after 2～3h, separate and remove solid matter and water, obtain oily matter.Wash oily matter with water, to the aqueous solution, be neutral.Oily matter is added to the water, with steam distillation to without oil droplet.Divide oil-yielding stratum, water layer extracts with benzene, merges after oil reservoir, and first normal pressure steams except benzene, and the fraction of 117～122 ℃ (2.3kp) is collected in rear underpressure distillation, obtains a bromoacetophenone.
3, between general, bromoacetophenone, acetic acid and catalyzer benzoyl peroxide add in there-necked flask, load onto return line, thermometer, and reflux 3h, adds catalyzer, continue backflow 3h.Steam except after most of acetic acid, pour in a large amount of water, stir to obtain the chloro-3 '-bromoacetophenone of brown oily crude product 2-.Filtration washing, then use benzene as solvent recrystallization, obtain the chloro-3 '-bromoacetophenone of white, needle-shaped crystals 2-(mp:65～67 ℃).
Embodiment:
Below in conjunction with specific embodiment, the invention will be further elaborated, but the invention is not restricted to these specific embodiments.
Real row one:
Between the preparation of bromoacetophenone: by 80ml48% Hydrogen bromide, 80ml water and 23g m-aminophenyl ethyl ketone, be chilled to 0～5 ℃ with icy salt solution, then under agitation splash into the solution (under liquid level) being made into by 12.2g Sodium Nitrite and 30ml water, and keep 0～8 ℃ of temperature of reaction, drip off, continue reaction 30min.The diazonium salt solution of above-mentioned system is poured in cold CuBr hydrochloric acid soln (27.5gCuBr+50ml Hydrogen bromide), be heated to 50～65 ℃, fully stir and place 2～3h.Solid matter and water are removed in separation, obtain oily matter.Wash oily matter with water, to the aqueous solution, be neutral.Oily matter is added to the water, with steam distillation to without oil droplet.Divide oil-yielding stratum, water layer extracts with benzene, merges after oil reservoir, and first normal pressure steams benzene, and the fraction of 117～122 ℃ (2.3kp) is collected in rear underpressure distillation, obtains bromoacetophenone between product (31.2g, content 99.6%, yield 95.2%).
The preparation of the chloro-3 '-bromoacetophenone of 2-: by 200ml acetic acid, 129g(0.65mol) between bromoacetophenone, 100g(0.75mol) NCS and 1g benzoyl peroxide be added in 1000ml there-necked flask, load onto return line, thermometer, stirring and refluxing 3h, add benzoyl peroxide 0.5g, continue backflow 3h.Steam except most of acetic acid, reaction solution, to entering in a large amount of water, is stirred to obtain to thick product (red-brown).Use benzene recrystallization, filtration washing and the dry chloro-3 '-bromoacetophenone of product 2-(131.1g, content 99.5%, yield 85.9%) that to obtain.This product is white, needle-shaped crystals (mp:65～67 ℃).
Real row two:
Between the preparation of bromoacetophenone: by 100ml 48% Hydrogen bromide, 80ml water and 23g m-aminophenyl ethyl ketone, be chilled to 0～10 ℃ with icy salt solution, then under agitation splash into the solution (under liquid level) being made into by 13.0g Sodium Nitrite and 30ml water, and keep 0～10 ℃ of temperature of reaction, drip off, continue reaction 30min.The diazonium salt solution of above-mentioned system is poured in cold CuBr hydrochloric acid soln (28.6gCuBr+60ml 48% Hydrogen bromide), be heated to 55～62 ℃, fully stir and place 2～3h.Solid matter and water are removed in separation, obtain oily matter.Wash oily matter with water, to the aqueous solution, be neutral.Oily matter is added to the water, with steam distillation to without oil droplet.Divide oil-yielding stratum, water layer extracts with benzene, merges after oil reservoir, and first normal pressure steams benzene, and the fraction of 117～122 ℃ (2.3kp) is collected in rear underpressure distillation, obtains bromoacetophenone 32.9g between product, content 99.3%, yield 96.3%).
The preparation of the chloro-3 '-bromoacetophenone of 2-: by 300ml acetic acid, 129g(0.65mol) between bromoacetophenone, 160g(0.90mol) NBS and 2g benzoyl peroxide be added in 1000ml there-necked flask, load onto return line, thermometer, stirring and refluxing 3h, add benzoyl peroxide 1.0g, continue backflow 3h.Steam except most of acetic acid, reaction solution, to entering in a large amount of water, is stirred to obtain to thick product (red-brown).Make solvent with chlorobenzene, recrystallization, filtration washing, dry, obtains the chloro-3 '-bromoacetophenone of product 2-(133.2g, content 99.4%, yield 87.2%).This product is white, needle-shaped crystals (mp:65～67 ℃).
Real row three:
Similar to the above-mentioned method of preparing the chloro-3 '-bromoacetophenone of 2-, can prepare the bromo-3 '-chloro-acetophenone of 2-.
The preparation manipulation of m chloroacetophenone is similar to example one, two.
The preparation of the bromo-3 '-chloro-acetophenone of 2-: by 200ml acetic acid, 100g(0.65mol) m chloroacetophenone, 100
(0.75mol) NCS and 1g benzoyl peroxide are added in 1000ml there-necked flask, load onto return line, thermometer, and stirring and refluxing 3h adds benzoyl peroxide 0.5g, continue backflow 3h.Steam except most of acetic acid, reaction solution, to entering in a large amount of water, is stirred to obtain to thick product (red-brown).Make solvent with benzene, recrystallization, filtration washing and the dry bromo-3 '-chloro-acetophenone of product 2-(132.3g, content 99.2%, yield 86.5%) that to obtain.This product is white, needle-shaped crystals (mp:51～52 ℃).
Real row four:
The preparation of m chloroacetophenone:
By 60ml concentrated hydrochloric acid, 60ml water and 23g m-aminophenyl ethyl ketone, be chilled to 0～5 ℃ with icy salt solution, then under agitation splash into the solution (under liquid level) being made into by 11.8g Sodium Nitrite and 20ml water, and keep 0～5 ℃ of temperature of reaction, drip off, continue reaction 20min.The diazonium salt solution of above-mentioned system is poured in cold CuCl hydrochloric acid soln (18gCuCl+55ml concentrated hydrochloric acid), be heated to 55～60 ℃, fully stir and place 2～3h.Solid matter and water are removed in separation, obtain oily matter.Wash oily matter with water, to the aqueous solution, be neutral.Oily matter is added to the water, with steam distillation to without oil droplet.Divide oil-yielding stratum, water layer extracts with benzene, merges after oil reservoir, and first normal pressure steams benzene, and the fraction of 100～102 ℃ (2.6kp) is collected in rear underpressure distillation, obtains product m chloroacetophenone (25.3g, content 99.6%, yield 96.9%).
The preparation of the bromo-3 '-chloro-acetophenone of 2-: by 230ml acetic acid, 100g(0.65mol) m chloroacetophenone, 134g(0.75mol) NBS and 1g benzoyl peroxide be added in 1000ml there-necked flask, load onto return line, thermometer, stirring and refluxing 3h, add benzoyl peroxide 0.5g, continue backflow 3h.Steam except most of acetic acid, reaction solution, to entering in a large amount of water, is stirred to obtain to thick product (red-brown).Filtration washing, dry, obtains the bromo-3 '-chloro-acetophenone of product 2-(132.2g, content 99.4%, yield 86.6%).This product is white, needle-shaped crystals mp:83～86 ℃.
Claims (5)
1. the synthetic method of the chloro-3 '-bromoacetophenone of 2-(bromoacetophenone between alpha-chloro), it is characterized in that take m-aminophenyl ethyl ketone as raw material, through diazotization reaction, methyl phenyl ketone diazonium hydrobromate between generation, through sandmeyer reaction, bromoacetophenone between generation, through alpha-chloro reaction, generates the chloro-3 '-bromoacetophenone of 2-.
2. according to the synthetic method of the chloro-3 '-bromoacetophenone of 2-claim (1) Suo Shu, it is characterized in that diazotizing reaction conditions is m-aminophenyl ethyl ketone and Hydrogen bromide, Sodium Nitrite, in the aqueous solution, react, suitable processing condition are normal pressure, 0～10 ℃ and reaction 4～8 hours, and the mol ratio of raw material is m-aminophenyl ethyl ketone: Hydrogen bromide: Sodium Nitrite=1:1.5～3.0:1.0～1.3.
3. according to the synthetic method of the chloro-3 '-bromoacetophenone of 2-claim (1) Suo Shu, it is characterized in that diazobenzene ethyl ketone hydrobromate and a cuprous bromide, in hydrobromic acid aqueous solution, react, suitable processing condition are normal pressure, 45～65 ℃ and reaction 2～5 hours, and the mol ratio of raw material is diazonium hydrobromate: Hydrogen bromide: cuprous bromide=1:2.3～3.1:1.1～1.3.
4. according to the synthetic method of the chloro-3 '-bromoacetophenone of 2-claim (1) Suo Shu, the condition that it is characterized in that alpha-chloro reaction is a bromoacetophenone and N-chlorosuccinimide, heating reflux reaction in organic solvent acetic acid or tetracol phenixin, suitable processing condition are normal pressure, reflux and reaction 5～13 hours, the mol ratio of raw material be between bromoacetophenone: acetic acid: NCS: benzoyl peroxide=1:3.5～5.0:1.0～1.2:0.002～0.01.
5. according to the synthetic method of the chloro-3 '-bromoacetophenone of 2-claim (1) Suo Shu, it is characterized in that this synthetic method can prepare the bromo-3 '-chloro-acetophenone of 2 – equally.
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| CN114573534A (en) * | 2022-03-30 | 2022-06-03 | 八叶草健康产业研究院(厦门)有限公司 | Preparation method of 5-bromobenzofuranone |
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| CN114573534A (en) * | 2022-03-30 | 2022-06-03 | 八叶草健康产业研究院(厦门)有限公司 | Preparation method of 5-bromobenzofuranone |
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Application publication date: 20140430 |