CN104016865B - The synthetic method of the ethyl benzoylacetate that phenolic hydroxyl group replaces - Google Patents
The synthetic method of the ethyl benzoylacetate that phenolic hydroxyl group replaces Download PDFInfo
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- CN104016865B CN104016865B CN201410014447.4A CN201410014447A CN104016865B CN 104016865 B CN104016865 B CN 104016865B CN 201410014447 A CN201410014447 A CN 201410014447A CN 104016865 B CN104016865 B CN 104016865B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The invention discloses the synthetic method of the ethyl benzoylacetate that a kind of phenolic hydroxyl group replaces, with phenolic hydroxyl group substituted benzene for main raw material, react in non-polar solvent with ethyl cyanacetate in the presence of a lewis acid catalyst, pass into hydrogen chloride gas, until do not absorb, after reacting completely, in the water that completely reacted material suction is cooled in advance, layering after cooling, after concentrating under reduced pressure, rectifying obtains the ethyl benzoylacetate that phenolic hydroxyl group replaces.The present invention is efficient, low cost and be applicable to large-scale industrial production, and the constant product quality obtained, content is greater than 99%.
Description
Technical field
The present invention relates to a kind of synthetic method of flavonoid medicine intermediate, particularly the synthetic method of ethyl benzoylacetate that replaces of a kind of phenolic hydroxyl group.
Background technology
Flavonoid compound is the Polyphenols natural product distributing very wide and important in a kind of plant, is almost present in all green plantss, plays an important role to the growth of plant, growth, Flowering and fruiting and the invasion and attack of resisting foreign matter.It has pharmacologically active widely, although strong not as good as alkaloid effect, but due to widely distributed, of a great variety, part of compounds content in plant is high, and most compound easily obtains in crystalline form, therefore more extensive to the research of this compounds, be the very important compound of a class in natural product.Present stage, most of flavonoid compound is obtained by scientist's synthetic, and as the important intermediate of flavonoid: the synthesis preparation of the ethyl benzoylacetate that phenolic hydroxyl group replaces is its top priority.Its general structural Formula is as follows:
Wherein, R is hydroxyl, a dihydroxyl or a trihydroxy-;
Document (J.M. Straley et al, Organic Synthesis, Collective, Vol, 4, p.415, publication date: on December 31st, 1963) disclose a kind of synthetic method of ethyl benzoylacetate, take Benzoyl chloride as starting raw material, react with methyl aceto acetate under alkaline solution effect, then obtain target compound under ammonium chloride solution effect.At present, synthetic route major part prepared by ethyl benzoylacetate compounds is all adopt this route, and just different contrivers exists difference in the preparation details often walked, cause preparing result and produce very large difference, such as yield, quality product, environmental pollution, production cost etc.
Summary of the invention
The synthetic method of the ethyl benzoylacetate that the object of the present invention is to provide a kind of phenolic hydroxyl group to replace, the method is efficient, low cost and be applicable to large-scale industrial production, and the constant product quality obtained, content is greater than 99%.
The technical solution adopted for the present invention to solve the technical problems is:
The synthetic method of the ethyl benzoylacetate that a kind of phenolic hydroxyl group replaces, with phenolic hydroxyl group substituted benzene for main raw material, react in non-polar solvent with ethyl cyanacetate in the presence of a lewis acid catalyst, pass into hydrogen chloride gas, until do not absorb, after reacting completely, in the water that completely reacted material suction is cooled in advance, layering after cooling, after concentrating under reduced pressure, rectifying obtains the ethyl benzoylacetate that phenolic hydroxyl group replaces.
The present invention adopts phenolic hydroxyl group substituted benzene that is inexpensive, that be easy to get and ethyl cyanacetate to be starting raw material, and under Lewis acid effect, a step obtains the ethyl benzoylacetate that product phenolic hydroxyl group of the present invention replaces.Reaction formula is as follows:
wherein, R is hydroxyl, a dihydroxyl or a trihydroxy-.
As preferably, described synthetic method concrete steps are as follows:
(1) in reactor, non-polar solvent is added successively, phenolic hydroxyl group substituted benzene and ethyl cyanacetate, (object of control temperature is excessive in order to prevent catalyzer from adding fashionable reaction generation heat to be here cooled to 5 ± 5 DEG C, cause production security low, therefore need to control lower temperature before catalyzer adds), then lewis acid catalyst is added, (object of control temperature is that reaction effect is good to control temperature 10 ± 10 DEG C here, react gentleer, reaction safety is good), reinforced complete, logical hydrogen chloride gas is not until absorb, 20 ± 5 DEG C of insulation reaction 22 ~ 24 hours,
(2) in another reactor, add water (object added water is for the ease of water-soluble substanceses such as separating catalysts), (object of control temperature is that the heat that prevents reaction product from producing is excessive to be here cooled to 5 ± 5 DEG C, affect security), add the material that step (1) has been reacted, at 40 ± 10 DEG C, (this step is in order to control temperature is moderate to control temperature, ensure security), reinforced complete, (intensification is to make catalyzer to dissolve preferably to be warming up to 55 ± 5 DEG C, be convenient to later separation) be incubated 30 ~ 35 minutes, then be cooled to 30 ± 5 DEG C (cooling is for the ease of follow-up stratification), stratification, separate organic layer, concentrating under reduced pressure obtains crude product, the ethyl benzoylacetate that phenolic hydroxyl group replaces is obtained after crude product rectifying.
As preferably, the mol ratio of described phenolic hydroxyl group substituted benzene and ethyl cyanacetate is 1:1.0 ~ 1.5.
As preferably, the mol ratio of described phenolic hydroxyl group substituted benzene and lewis acid catalyst is 1:2 ~ 3.
As preferably, described phenolic hydroxyl group substituted benzene is phenol, Resorcino or phloroglucinol.
As preferably, described lewis acid catalyst is aluminum trichloride (anhydrous), Anhydrous Ferric Chloride, Zinc Chloride Anhydrous, boron trifluoride diethyl etherate or titanium tetrachloride.
As preferably, described non-polar solvent is selected from one or more in methylene dichloride, ethylene dichloride, tetracol phenixin, toluene.
As preferably, described non-polar solvent consumption be the 2-4 of phenolic hydroxyl group substituted benzene weight doubly.
As preferably, the consumption of described water be the 4-8 of phenolic hydroxyl group substituted benzene weight doubly.
The invention has the beneficial effects as follows: with phenolic hydroxyl group substituted benzene for starting raw material; one step obtains the ethyl benzoylacetate that phenolic hydroxyl group replaces; have the advantages such as raw material is inexpensive, route is short, yield is high, applicable large-scale production, the constant product quality obtained, content is greater than 99%.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail.
In the present invention, if not refer in particular to, the raw material adopted and equipment etc. all can be buied from market or this area is conventional.Method in following embodiment, if no special instructions, is the ordinary method of this area.
A synthetic method for the ethyl benzoylacetate that phenolic hydroxyl group replaces, concrete steps are as follows:
(1) in reactor, add non-polar solvent, phenolic hydroxyl group substituted benzene and ethyl cyanacetate successively, be cooled to 5 ± 5 DEG C, then add lewis acid catalyst, control temperature 10 ± 10 DEG C, reinforced complete, logical hydrogen chloride gas until do not absorb, 20 ± 5 DEG C of insulation reaction 22 ~ 24 hours.
The mol ratio of described phenolic hydroxyl group substituted benzene and ethyl cyanacetate is 1:1.0 ~ 1.5.The mol ratio of described phenolic hydroxyl group substituted benzene and lewis acid catalyst is 1:2 ~ 3.Described phenolic hydroxyl group substituted benzene is phenol, Resorcino or phloroglucinol.Described lewis acid catalyst is aluminum trichloride (anhydrous), Anhydrous Ferric Chloride, Zinc Chloride Anhydrous, boron trifluoride diethyl etherate or titanium tetrachloride.Described non-polar solvent is selected from one or more in methylene dichloride, ethylene dichloride, tetracol phenixin, toluene.Described non-polar solvent consumption is 2-4 times of phenolic hydroxyl group substituted benzene weight.
(2) in another reactor, add water, the consumption of described water is 4-8 times of phenolic hydroxyl group substituted benzene weight,
Be cooled to 5 ± 5 DEG C, add the material that step (1) has been reacted, control temperature is at 40 ± 10 DEG C, reinforced complete, be warming up to 55 ± 5 DEG C of insulations 30 ~ 35 minutes, be then cooled to 30 ± 5 DEG C, stratification, separate organic layer, concentrating under reduced pressure obtains crude product, obtains the ethyl benzoylacetate that phenolic hydroxyl group replaces after crude product rectifying.
Several object lesson is exemplified to illustrate working method of the present invention below the present invention:
Embodiment 1
To in reactor, add 120kg methylene dichloride, 38.5kg phenol and 47kg ethyl cyanacetate successively.Be cooled to 5 DEG C, slowly add 106kg aluminum trichloride (anhydrous) in batches, control temperature 10 DEG C, feed in raw material and finish, logical hydrogen chloride gas is not until absorb.20 DEG C of insulation reaction 24 hours, add the tap water of 220kg in another reactor, and logical icy salt solution temperature is down to 5 DEG C, and in this still of material suction good for insulation reaction, slow suction, control temperature is at 40 DEG C, reinforced complete, is warming up to 55 DEG C of insulations 30 minutes.Insulation terminates, and logical cooling water temperature to 30 DEG C, stratification, separates organic layer, and concentrating under reduced pressure obtains crude product, and rectifying obtains para hydroxybenzene malonaldehydic acid ethyl ester 68kg, yield 78%.Product content (GC)=99.6%.
Embodiment 2
To in reactor, add 120kg methylene dichloride, 38.5kg phenol and 56.4kg ethyl cyanacetate successively.Be cooled to 5 DEG C, slowly add 110kg Zinc Chloride Anhydrous in batches, control temperature 10 DEG C, feed in raw material and finish, logical hydrogen chloride gas is not until absorb.20 DEG C of insulation reaction 24 hours, add the tap water of 220kg in another reactor, and logical icy salt solution temperature is down to 5 DEG C, and in this still of material suction good for insulation reaction, slow suction, control temperature is at 40 DEG C, reinforced complete, is warming up to 55 DEG C of insulations 30 minutes.Insulation terminates, and logical cooling water temperature to 30 DEG C, stratification, separates organic layer, and concentrating under reduced pressure obtains crude product, and rectifying obtains para hydroxybenzene malonaldehydic acid ethyl ester 72kg, yield 82.5%.Product content (GC)=99.5%.
Embodiment 3
To in reactor, add 120kg ethylene dichloride, 45kg Resorcinol and 47kg ethyl cyanacetate successively.Be cooled to 5 DEG C, slowly add 106kg aluminum trichloride (anhydrous) in batches, control temperature 10 DEG C, feed in raw material and finish, logical hydrogen chloride gas is not until absorb.20 DEG C of insulation reaction 22 hours, add the tap water of 220kg in another reactor, and logical icy salt solution temperature is down to 5 DEG C, and in this still of material suction good for insulation reaction, slow suction, control temperature is at 40 DEG C, reinforced complete, is warming up to 55 DEG C of insulation half an hour.Question response terminates, and logical cooling water temperature to 30 DEG C, layering, separates organic layer, and concentrating under reduced pressure obtains crude product, and rectifying obtains 2,4-dihydroxybenzoyl ethyl acetate 71.5kg, yield 78%.Product content (GC)=99.5%.
Embodiment 4
To in reactor, add 120kg ethylene dichloride, 45kg Resorcinol and 56.4kg ethyl cyanacetate successively.Be cooled to 5 DEG C, slowly add 113kg boron trifluoride diethyl etherate in batches, control temperature 10 DEG C, feed in raw material and finish, logical hydrogen chloride gas is not until absorb.20 DEG C of insulation reaction 22 hours, add the tap water of 220kg in another reactor, and logical icy salt solution temperature is down to 5 DEG C, and in this still of material suction good for insulation reaction, slow suction, control temperature is at 40 DEG C, reinforced complete, is warming up to 55 DEG C of insulation half an hour.Question response terminates, and logical cooling water temperature to 30 DEG C, layering, separates organic layer, and concentrating under reduced pressure obtains crude product, and rectifying obtains 2,4-dihydroxybenzoyl ethyl acetate 70kg, yield 76.4%.Product content (GC)=99.4%.
Embodiment 5
To in reactor, add 120kg ethylene dichloride, 51.6kg Phloroglucinol and 47kg ethyl cyanacetate successively.Be cooled to 0 DEG C, slowly add 110kg Zinc Chloride Anhydrous in batches, control temperature 0 DEG C, feed in raw material and finish, logical hydrogen chloride gas is not until absorb.15 DEG C of insulation reaction 24 hours, add the tap water of 220kg in another reactor, and logical icy salt solution temperature is down to 0 DEG C, and in this still of material suction good for insulation reaction, slow suction, control temperature is at 30 DEG C, reinforced complete, is warming up to 50 DEG C of insulation 35min.Question response terminates, and logical cooling water temperature to 25 DEG C, layering, separates organic layer, and concentrating under reduced pressure obtains crude product, and rectifying obtains 2,4,6-trihydroxy-ethyl benzoylacetate 73kg, yield 74%.Product content (GC)=99.2%.
Embodiment 6
To in reactor, add 60kg methylene dichloride, 60kg ethylene dichloride, 51.6kg Phloroglucinol and 56.4kg ethyl cyanacetate successively.Be cooled to 10 DEG C, slowly add 150kg titanium tetrachloride in batches, control temperature 20 DEG C, feed in raw material and finish, logical hydrogen chloride gas is not until absorb.25 DEG C of insulation reaction 24 hours, add the tap water of 220kg in another reactor, and logical icy salt solution temperature is down to 10 DEG C, and in this still of material suction good for insulation reaction, slow suction, control temperature is at 50 DEG C, reinforced complete, is warming up to 60 DEG C of insulation half an hour.Question response terminates, and logical cooling water temperature to 35 DEG C, layering, separates organic layer, and concentrating under reduced pressure obtains crude product, and rectifying obtains 2,4,6-trihydroxy-ethyl benzoylacetate 63kg, yield 64%.Product content (GC)=99.1%.
Above-described embodiment is one of the present invention preferably scheme, not does any pro forma restriction to the present invention, also has other variant and remodeling under the prerequisite not exceeding the technical scheme described in claim.
Claims (8)
1. the synthetic method of the ethyl benzoylacetate of a phenolic hydroxyl group replacement, it is characterized in that: with phenolic hydroxyl group substituted benzene for main raw material, react in non-polar solvent with ethyl cyanacetate in the presence of a lewis acid catalyst, pass into hydrogen chloride gas, until do not absorb, after reacting completely, in the water that completely reacted material suction is cooled in advance, layering after cooling, after concentrating under reduced pressure, rectifying obtains the ethyl benzoylacetate that phenolic hydroxyl group replaces;
Described synthetic method concrete steps are as follows:
(1) in reactor, add non-polar solvent, phenolic hydroxyl group substituted benzene and ethyl cyanacetate successively, be cooled to 5 ± 5 DEG C, then add lewis acid catalyst, control temperature 10 ± 10 DEG C, reinforced complete, logical hydrogen chloride gas until do not absorb, 20 ± 5 DEG C of insulation reaction 22 ~ 24 hours;
(2) in another reactor, water is added, be cooled to 5 ± 5 DEG C, add the material that step (1) has been reacted, control temperature is at 40 ± 10 DEG C, reinforced complete, be warming up to 55 ± 5 DEG C of insulations 30 ~ 35 minutes, then be cooled to 30 ± 5 DEG C, stratification, separate organic layer, concentrating under reduced pressure obtains crude product, obtains the ethyl benzoylacetate that phenolic hydroxyl group replaces after crude product rectifying.
2. synthetic method according to claim 1, is characterized in that: the mol ratio of described phenolic hydroxyl group substituted benzene and ethyl cyanacetate is 1:1.0 ~ 1.5.
3. synthetic method according to claim 1, is characterized in that: the mol ratio of described phenolic hydroxyl group substituted benzene and lewis acid catalyst is 1:2 ~ 3.
4. synthetic method according to claim 1, is characterized in that: described phenolic hydroxyl group substituted benzene is phenol, Resorcino or phloroglucinol.
5. synthetic method according to claim 1, is characterized in that: described lewis acid catalyst is aluminum trichloride (anhydrous), Anhydrous Ferric Chloride, Zinc Chloride Anhydrous, boron trifluoride diethyl etherate or titanium tetrachloride.
6. synthetic method according to claim 1, is characterized in that: described non-polar solvent is selected from one or more in methylene dichloride, ethylene dichloride, tetracol phenixin, toluene.
7. synthetic method according to claim 1, is characterized in that: described non-polar solvent consumption is 2-4 times of phenolic hydroxyl group substituted benzene weight.
8. synthetic method according to claim 1, is characterized in that: the consumption of described water is 4-8 times of phenolic hydroxyl group substituted benzene weight.
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| US3825574A (en) * | 1972-12-04 | 1974-07-23 | Warner Lambert Co | Process for preparing substituted chromone-3-carbonitriles,carboxamides and carboxylic acids |
| JPS55136251A (en) * | 1979-04-12 | 1980-10-23 | Oriental Shashin Kogyo Kk | Novel keto ester compound |
| ES2083580T3 (en) * | 1990-06-13 | 1996-04-16 | Arnold Glazier | PHOSPHORIC DRUGS. |
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| Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2);Chandrakala Pidathala et al.;《Journal of Medicinal Chemistry》;20120224;第55卷(第5期);第1831-1843页 * |
| The silver salt of 12-tungstophosphoric acid. A mild and selective catalyst for the synthesis of β-ketoesters via C-H insertion;J.S. Yadav et al.;《Catalysis Communications》;20080630;第9卷(第14期);第2361-2364页 * |
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