CN104341382A - Synthesis method of isocoumarin derivative - Google Patents
Synthesis method of isocoumarin derivative Download PDFInfo
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- CN104341382A CN104341382A CN201410285978.7A CN201410285978A CN104341382A CN 104341382 A CN104341382 A CN 104341382A CN 201410285978 A CN201410285978 A CN 201410285978A CN 104341382 A CN104341382 A CN 104341382A
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- isocoumarin
- dimethoxy
- hexyl
- cuprous
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
Abstract
The invention discloses a synthesis method of an isocoumarin derivative. The method comprises the following steps: adding 3-hexyl-4-cyan-6,7-dimethoxy isocoumarin (A), a cuprous catalyst and acetaldoxime (B) in a reaction vessel, adding a solvent N,N-dimethyl formamide (DMF), stirring and refluxing; reacting for 1 hour, cooling, filtering reaction solution in vacuum, and adding a certain amount of water in the filtrate, filtering separated solid in vacuum, drying and low-temperature crystalizing obtained coarse product so as to obtain a target product 3-hexyl-4-acylamoni-6,7-dimethoxy isocoumarin (C). The method for translating the isocoumarin into acylamino is scientific and reasonable, the step is simple, the reaction time is short, the selectivity is good, the translation rate is high, the product is easy to purify; cuprous salt is firstly used as the catalyst, and the catalysis efficiency is high in comparison with the reported cupric, in particular, the cuprous has good catalysis effect on cyan hydrolysis with large steric hindrance.
Description
Technical field
The present invention relates to a kind of preparation of different coumarin derivative and the method for separation and purification thereof.
Background technology
Compound 4-(2-aminopropan amide group)-3,4,5,6,7,8,9,10-octahydro-5,6, the 8-trihydroxy--3-methyl Isocoumarin extracted from Huang Dingju, its structure is as follows:
This compound has certain weeding activity, and according to above structure, synthesized compound 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin by the method for organic synthesis, its structural formula is as follows:
Amide group structure in its structure is obtained by cyan-hydrolysis, conventional cyan-hydrolysis condition generally needs to carry out under strong acid or basic conditions, owing to there being the structure of hexa-atomic fourth finger in Isocoumarin, under strong acid or basic conditions, ester bond is easily hydrolyzed, and the hydrolysis end product of cyano group is carboxylic acid under strong acid and strong base condition, acid amides is its intermediate product, and condition is wayward.Xiao-Yun Ma, Ying He, Yu-Lin Hu, Ming Lu.Tetrahedron Letters 53 (2012) 449 – 452. describes a kind of ethylidenehydroxylamine and react with cyano compound the method preparing acid amides under cupric salt catalysis, cyano group orientation can be converted into acid amides by this method, but its be applied in Isocoumarin there is long reaction time, transform thoroughly, the problem such as product and impurity that purifying not easily separated.
summary of the invention:
The object of the invention is to solve the deficiency existed in above-mentioned reaction, Reaction time shorten improves transformation efficiency.
The synthetic method of a kind of different coumarin derivative provided by the invention, its step is as follows: cyano group Isocoumarin (A) and ethylidenehydroxylamine (B) react under copper catalyst catalysis, obtain acid amides Isocoumarin (C).Described compd A, B, C-structure formula are shown below:
Above-mentionedly prepare in the method for different coumarin derivative, described copper catalyst is cuprous catalysis agent, and described cuprous catalysis agent can be CuCl, CuI, CuBr, Cu
2any one in O.
Solvent needed for the above-mentioned reaction preparing different coumarin derivative can be any one in methylene dichloride, ethyl acetate, DMF, toluene, and also can be mixed in proportion for DMF and other several solvents, its blending ratio is methylene dichloride: DMF=1:4; Ethyl acetate: DMF=1:2. does not all need through Non-aqueous processing when above-mentioned solvent uses, and can directly use.
The above-mentioned mass ratio preparing the reaction material used of different coumarin derivative can be A:B:C=1:0.38:0.25
The above-mentioned temperature of reaction preparing different coumarin derivative can be 100-160 DEG C, as 110 DEG C, 140 DEG C, 160 DEG C.The described reaction times is 0.5-1h.
Above-mentioned prepare the reaction terminating of different coumarin derivative after need to obtain the product after purifying through the step such as suction filtration, low temperature crystallization.
The above-mentioned reaction preparing different coumarin derivative, adds a certain amount of water after having reacted wherein, suction filtration after having a large amount of solid to separate out.Low temperature crystallization solvent for use is ethyl acetate, and low temperature crystallization temperature is-20 DEG C ~-10 DEG C.
The preparation method of different coumarin derivative provided by the invention is scientific and reasonable, has reaction times short, the advantage such as transformation efficiency is high, product is single, inclusion-free is easily separated compared with method described in forefathers.
Accompanying drawing explanation
Fig. 1: 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin nucleus magnetic resonance H1 composes.
Fig. 2: 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin nucleus magnetic resonance C13 composes.
Embodiment
The present invention is set forth further below in conjunction with specific embodiment.Following specific embodiment is only for being specifically described the present invention, but following examples are not limited to protection scope of the present invention, and the improvement made according to the present invention of those skilled in the art and adjustment, still belong to protection scope of the present invention in actual applications.
Embodiment 1
Make catalyzer DMF with cuprous iodide and make solvent
3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin 3.94g, cuprous iodide 1g, DMF15ml, ethylidenehydroxylamine 3g is added successively, with electric mantle reflux 0.5h in 100ml reaction vessel.Suction filtration after reaction system cooling, add water in downward metafiltration liquid 30ml, has a large amount of solid to separate out, suction filtration, with the solid that 20ml acetic acid ethyl dissolution suction filtration goes out, after ebuillition of heated, suction filtration discards upper strata black solid, and lower floor's filtrate adds 8ml ethyl acetate and is placed on-15 DEG C of freeze overnight in refrigerator after revolving evaporate to dryness.Suction filtration, obtains beige solid 2.4g.Fusing point 159-162.1 DEG C.The result that nucleus magnetic resonance characterizes is: 1H NMR (600 MHz, CDCl3): δ 7.57 (s, 1H, ArH), 7.29 (s, 2H, NH2) 6.95 (s, 1H, ArH), 3.99 [s, 3H, (OCH3)], 3.97 [s, 3H, (OCH3)], 2.69 (t, J=7.5 Hz, 2H, CH2), 1.33-1.31 (m, 2H, CH2), 1.40-1.38 [m, 6H, (CH2) 3], 0. 90 (t, J=6.9 Hz, 3H, CH3). 13CNMR (600 MHz, CDCl3): δ 167.45, 161.69, 155.48, 155.42 149.67, 130.27, 112.83, 112.68, 109.47, 104.5, 56.34, 56.25, 32.1, 31.46, 28.96, 27.7, 22.48, 14.0. MS, m/z (%): 315.2 (M+, 100).
Embodiment 2
Catalyzer DMF is made and ethyl acetate makes solvent with cuprous iodide
3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin 3.94g, cuprous iodide 1g, DMF10ml+ ethyl acetate 5ml, ethylidenehydroxylamine 3g is added successively, with electric mantle reflux 1h in 100ml reaction vessel.Suction filtration after reaction system cooling, add water in downward metafiltration liquid 30ml, has a large amount of solid to separate out, suction filtration, with the solid that 20ml ethyl acetate heating for dissolving suction filtration goes out, suction filtration discards upper strata solid while hot, and lower floor's filtrate adds 8ml ethyl acetate and is placed on-15 DEG C of freeze overnight in refrigerator after revolving evaporate to dryness.Suction filtration, obtains beige solid 2.75g.Fusing point 160-162.3 DEG C, it is consistent with embodiment 1 that high performance liquid chromatography detects retention time.
Embodiment 3
Cuprous bromide makes catalyzer
3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin 3.94g, cuprous bromide 1g, DMF15ml, ethylidenehydroxylamine 3g is added successively, with electric mantle reflux 45min in 100ml reaction vessel.Suction filtration after reaction system cooling, add water in downward metafiltration liquid 30ml, has a large amount of solid to separate out, suction filtration, and the solid gone out with 8ml acetic acid ethyl dissolution suction filtration is placed on-15 DEG C of freeze overnight in refrigerator.Suction filtration, obtains beige solid 3.19g.Fusing point 161-163.3 DEG C, high performance liquid chromatography retention time is consistent with embodiment 1.
Embodiment 4
Cuprous bromide is made catalyzer DMF+ ethyl acetate and is made solvent
In 100ml reaction vessel, add 3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin, cuprous bromide, DMF10ml+5ml ethyl acetate, ethylidenehydroxylamine successively, with electric mantle reflux 1h, add ethylidenehydroxylamine, continue reaction 1.5h.Suction filtration after reaction system cooling, add water in downward metafiltration liquid 30ml, has a large amount of solid to separate out, suction filtration, and the solid gone out with 8ml acetic acid ethyl dissolution suction filtration is placed on-15 DEG C of freeze overnight in refrigerator.Suction filtration, obtains beige solid 3.1g.Fusing point 161-162.9 DEG C.High performance liquid chromatography retention time is consistent with embodiment 1.
Embodiment 5
Catalyzer made by cuprous chloride
3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin 3.94g, cuprous chloride 2g, DMF15ml, ethylidenehydroxylamine 3g is added successively, with electric mantle reflux 1h in 100ml reaction vessel.Suction filtration after reaction system cooling, add water in downward metafiltration liquid 30ml, has a large amount of solid to separate out, suction filtration, and the solid gone out with 8ml acetic acid ethyl dissolution suction filtration is placed on-15 DEG C of freeze overnight in refrigerator.Suction filtration, obtains beige solid 2.77g.Fusing point 160-162.5 DEG C.High performance liquid chromatography retention time is consistent with embodiment 1.
Embodiment 6
Cuprous chloride is made catalyzer DMF+ ethyl acetate and is made solvent
3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin 3.94g, cuprous chloride 2g, DMF10ml+5ml ethyl acetate, ethylidenehydroxylamine 3g is added successively, with electric mantle reflux 1h in 100ml reaction vessel.Suction filtration after reaction system cooling, add water in downward metafiltration liquid 30ml, has a large amount of solid to separate out, suction filtration, and the solid gone out with 8ml acetic acid ethyl dissolution suction filtration is placed on-15 DEG C of freeze overnight in refrigerator.Suction filtration, obtains beige solid 2.6g.Fusing point 159.3-163 DEG C, high performance liquid chromatography retention time is consistent with embodiment 1.
A kind of preparation of different coumarin derivative of the present invention and the method for separation and purification thereof are described by specific embodiment, those skilled in the art can use for reference content of the present invention, the links such as appropriate change raw material, processing condition realize other object corresponding, its relevant change does not all depart from content of the present invention, all similar replacements and change will become apparent to those skilled in the art that and be all deemed to be included within scope of the present invention.
Claims (9)
1. prepare compound 3-hexyl-4-amide group-6 for one kind, the method of 7-dimethoxy Isocoumarin, comprise the steps: compound ethylidenehydroxylamine and compound 3-hexyl-4-cyano group-6 under cuprous salt catalyst action, after 7-dimethoxy Isocoumarin reacts in the solution, separation and purification obtains compound 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin.
2. method according to claim 1, is characterized in that described cuprous salt catalyzer is cuprous iodide, cuprous chloride, cuprous bromide, Red copper oxide.
3. method according to claim 1, it is characterized in that described solvent is that DMF mixes with ethyl acetate, and the volume ratio of ethyl acetate and DMF is 1:1-1:3, does quencher after completion of the reaction with water.
4. method according to claim 1, is characterized in that the weight ratio of described 3-hexyl-4-cyano group-6,7-dimethoxy Isocoumarin, ethylidenehydroxylamine and cuprous salt is 1:0.38:0.25.
5. method according to claim 1, it is characterized in that the temperature of reaction of described reaction is 100 DEG C-160 DEG C, the reaction times is 0.5-1h.
6. the method according to right 1, is characterized in that the purification procedures of compound 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin can adopt extraction, column chromatography, concentrated or precipitation, extraction, low temperature crystallization.
7. the method according to right 6, it is characterized in that compound 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin column chromatography elutriant used is ethyl acetate, sherwood oil, its ratio is 4:6.
8. the method according to right 6, is characterized in that the solvent that compound 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin precipitation, extraction, low temperature crystallization adopt is ethyl acetate.
9. the method according to right 6, is characterized in that compound 3-hexyl-4-amide group-6,7-dimethoxy Isocoumarin low temperature crystallization temperature is-20 ~-10 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727346A (en) * | 2017-04-14 | 2018-11-02 | 河北农业大学 | A kind of preparation method and purposes of isocoumarin pyridinium salt |
| CN111253358A (en) * | 2020-02-10 | 2020-06-09 | 河南理工大学 | Synthetic method of isocoumarin aromatic ether compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224482A (en) * | 2013-04-10 | 2013-07-31 | 上海交通大学 | Isocoumarin compound, derivatives and synthesis method thereof |
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- 2014-06-23 CN CN201410285978.7A patent/CN104341382A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224482A (en) * | 2013-04-10 | 2013-07-31 | 上海交通大学 | Isocoumarin compound, derivatives and synthesis method thereof |
Non-Patent Citations (3)
| Title |
|---|
| CHARLES WIENER, COLLIN H.SCHROER等: "The Synthesis of Various 3-Substituted-4-alkylcoumarin", 《JOUIRNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| M.P.NEMERYUK，等: "CONVERSIONS OF COUMARINS AC OF MALONIC ACID HYDRAZIDE AND AMIDE DERIVATIVES WITH 3-ACYL(3-CYANO, 3-ETHOXYCARBONYL)COUMARINSCOMPANIED BY INTERMEDIATE OPENING AND RECYCLIZATION OF THE LACTONE RING.", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
| XIAO-YUN MA，等: "Copper(II)-catalyzed hydration of nitriles with the aid of acetaldoxime", 《TETRAHEDRON LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727346A (en) * | 2017-04-14 | 2018-11-02 | 河北农业大学 | A kind of preparation method and purposes of isocoumarin pyridinium salt |
| CN111253358A (en) * | 2020-02-10 | 2020-06-09 | 河南理工大学 | Synthetic method of isocoumarin aromatic ether compound |
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Application publication date: 20150211 |