CN113214205B - Preparation method of chromone derivative - Google Patents
Preparation method of chromone derivative Download PDFInfo
- Publication number
- CN113214205B CN113214205B CN202110380660.7A CN202110380660A CN113214205B CN 113214205 B CN113214205 B CN 113214205B CN 202110380660 A CN202110380660 A CN 202110380660A CN 113214205 B CN113214205 B CN 113214205B
- Authority
- CN
- China
- Prior art keywords
- compound
- copper
- formula
- reaction
- hydroxybenzoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Abstract
The invention discloses a preparation method of a chromone derivative, which comprises the following steps: in the presence of a copper compound, reacting an o-hydroxybenzoyl acetylene compound with a diazo compound to obtain a chromone derivative. The invention obtains the chromone derivative by selecting a proper reaction substrate and then selecting and cooperating a proper catalyst and a ligand, has simple reaction conditions, obtains good yield, provides a new synthetic route for preparing the chromone compound, and has good application value and potential in industry and scientific research.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of a chromone derivative.
Background
The isolation and structural modification of natural products are one of the important ways to find and discover new drugs. Chromones are also known as chromones, known by the chemical name benzopyran-4-one. Chromone itself has not been isolated from natural sources to date, but derivatives are widely found in nature, some being colored substances, and hence the name chromone. Chromone belongs to a secondary metabolite of plants, and has various physiological activities, such as anti-inflammatory, anti-platelet aggregation, liver protection, anti-tumor, anti-oxidation, anti-allergy and the like. Therefore, synthetic chemistry of chromone derivatives has attracted considerable attention. There remains a need to discover novel chromone derivatives and novel synthetic methods therefor.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a preparation method of the chromone derivative, provides a new synthetic route for preparing the chromone compound, and can obtain good yield by optimizing conditions.
Specifically, the technical scheme adopted by the invention is as follows:
a method for preparing a chromone derivative comprises the following steps:
in the presence of a copper compound, reacting an o-hydroxybenzoyl acetylene compound shown as a formula (II) and a diazo compound shown as a formula (III) to obtain the chromone derivative shown as a formula (I),
the R is1、R2Independently selected from H, ester group, cyano, nitro, hydroxy, phenyl, methylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl or halo C1-C6Any one of alkoxy groups.
Wherein, C1-C6Alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms, which includes C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6Alkyl, which can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl, and the like.
Wherein, C1-C6Alkoxy means C1-C6A group in which an alkyl group is bonded to an O atom.
Wherein, the meaning of the halogen refers to halogen elements and can be F, Cl, Br or I.
Wherein is halogenated C1-C6Alkyl means C substituted by halogen1-C6Alkyl groups, which may be trifluoromethyl, pentafluoroethyl, difluoromethyl, chloromethyl, and the like.
Wherein is halo C1-C6The meaning of alkoxy means C substituted by halogen1-C6The alkoxy group may be trifluoromethoxy, pentafluoroethoxy, difluoromethoxy, chloromethoxy, etc.
In the preparation method, firstly, a diazo compound (III) generates a copper carbene intermediate A under the catalysis of copper, then the diazo compound (III) and an o-hydroxybenzoyl acetylene compound (II) are subjected to insertion reaction to obtain an intermediate B, then intramolecular nucleophilic addition reaction is carried out to obtain an intermediate C, and finally, the chromone derivative (I) is obtained through isomerization, wherein the reaction mechanism is as follows:
in some embodiments of the invention, R is2Is C1-C6alkoxy-OR3Said R is3Is selected from C1-C6An alkyl group.
In some embodiments of the invention, the copper compound comprises copper acetate (Cu (OAc)2) Copper chloride (CuCl)2) Copper bromide (CuBr)2) Copper acetylacetonate (Cu (acac)2) Copper trifluoroacetate (Cu (TFA)2) Copper trifluoromethanesulfonate (Cu (OTf)2) Preferably, the copper catalyst is copper iodide (CuI) or copper chloride (CuCl), and most preferably, the copper catalyst is copper iodide (CuI).
In some embodiments of the invention, the reaction is carried out in the presence of a ligand. The ligand comprises N, N-Dimethylformamide (DMF) and triethylamine (Et)3N), N-tributylamine (nBu)3N), tri-tert-butylamine (tBu)3N), 2-fluoropyridine (2-FPy), 2-chloropyridine (2-ClPy), 2-bromopyridine (2-BrPy), 2-iodopyridine (2-BrPy), tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl]Any one or more of amine (TBTA) and 1, 10-phenanthroline (Phen), preferably triethylamine and tri [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl]Amine (TBTA) or N, N-Dimethylformamide (DMF), most preferably triethylamine.
In some embodiments of the invention, the reaction is carried out in an organic solvent. The organic solvent includes any one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dichloromethane, chlorobenzene, benzene, xylene, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), preferably dichloromethane.
In some embodiments of the invention, the molar ratio of the o-hydroxybenzoylacetylene compound (II) to the copper compound is 1:0.05-0.2, for example 1:0.05, 1:0.1 or 1: 0.2.
In some embodiments of the invention, the molar ratio of the o-hydroxybenzoylacetylene compound (II) to the ligand is 1:0.1-2, and may be, for example, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5 or 1:2.
In some embodiments of the invention, the molar ratio of the o-hydroxybenzoyl acetylene compound (II) to the diazo compound (III) is 1:1 to 3, and may be, for example, 1:1, 1:1.5 or 1: 3.
In some embodiments of the invention, the ratio of the o-hydroxybenzoylacetylene compound (II) to the solvent is 1mmol:5-15mL, such as 1mmol:5mL, 1mmol:8mL, 1mmol:10mL, 1mmol:12mL or 1mmol:15 mL.
In some embodiments of the invention, the temperature of the reaction is 25 to 80 ℃, for example 25 ℃, 40 ℃, 60 ℃ or 80 ℃ and the reaction time is 0.5 to 8 hours, for example 0.5, 1,2, 4 or 8 hours.
In some embodiments of the present invention, the reaction further comprises a post-treatment step after the reaction is finished. The post-treatment comprises any one treatment means or combination of a plurality of treatment means in extraction, concentration, crystallization, recrystallization and column chromatography purification.
As an exemplary post-treatment means, for example, there can be mentioned: after the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh-300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-10, so as to obtain the chromone derivative in the formula (I).
Compared with the prior art, the invention has the following beneficial effects:
the invention obtains the chromone derivative shown in the formula (I) by selecting a proper reaction substrate and then selecting and cooperating a proper catalyst and a ligand, has simple reaction conditions, obtains good yield, provides a new synthetic route for preparing the chromone compound, and has good application value and potential in industry and scientific research.
Detailed Description
The technical scheme of the invention is further illustrated by the following specific examples.
Example 1
The compound of the above formula (II), (III), copper iodide (CuI) and triethylamine were added to methylene chloride, and then heated to 60 ℃ and stirred at that temperature for a sealing reaction for 4 hours.
Wherein the molar ratio of the compound shown in the formula (II) to cuprous iodide (CuI) is 1: 0.1; the molar ratio of the compound of the formula (II) to triethylamine is 1:0.1, and the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1: 1.5; the ratio of compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) is 1: 8.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh-300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5, so as to obtain a target product of the compound (C) in the formula (I) of a yellow liquid18H14O4) The yield was 88.7%.
Nuclear magnetic resonance:1HNMR(400MHz,CDCl3)δ8.18-8.15(m,1H),7.65-7.63(m,1H),7.43-7.38(m,2H),6.29(s,1H),4.22(q,J＝6.8Hz,2H),3.63(s,2H),1.27(t,J＝6.8Hz,3H)。
13CNMR(100MHz,CDCl3)δ178.2,167.5,156.5,133.9,125.8,125.4,123.7,118.1,112.4,62.0,40.4,14.2。
example 2
The reaction formula is the same as that of example 1, and the specific preparation method comprises the following steps:
the compound of the above formula (II), (III), copper iodide (CuI) and triethylamine were added to methylene chloride, and then the temperature was raised to 80 ℃ and the reaction was stirred at that temperature and sealed for 8 hours.
Wherein the molar ratio of the compound shown in the formula (II) to the cuprous iodide (CuI) is 1: 0.2; the molar ratio of the compound shown in the formula (II) to triethylamine is 1: 0.2; the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:2: 2; the ratio of compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) is 1: 10.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:6, so as to obtain the target product, namely the compound (C) of the formula (I)18H14O4) The yield was 90.3%.
The nmr data were the same as in example 1.
Example 3
The reaction formula is the same as that of example 1, and the specific preparation method comprises the following steps:
the compound of the above formula (II), (III), copper iodide (CuI) and triethylamine were added to DMF, followed by stirring and sealing reaction at room temperature for 2 hours.
Wherein the molar ratio of the compound shown in the formula (II) to the cuprous iodide (CuI) is 1: 0.15; the molar ratio of the compound shown in the formula (II) to triethylamine is 1: 0.3; the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:1.2: 1.2; the ratio of compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) is 1: 8.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh-300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein BThe volume ratio of the ethyl acetate to the petroleum ether is 1:8, so that the target product, namely the compound (C) of the formula (I)18H14O4) The yield was 87.5%.
The nmr data were the same as in example 1.
Example 4
The reaction formula is the same as that of example 1, and the specific preparation method comprises the following steps:
the compound of the above formula (II), (III), copper iodide (CuI) and triethylamine are added to DMF, and then the temperature is raised to 70 ℃, and the reaction is stirred and sealed for 12 hours at the temperature.
Wherein the molar ratio of the compound shown in the formula (II) to the cuprous iodide (CuI) is 1: 0.25; the molar ratio of the compound shown in the formula (II) to triethylamine is 1: 0.5; the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:2.5: 2.5; the ratio of compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) was 1: 12.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:7, so as to obtain the target product, namely the compound (C) of the formula (I)18H14O4) The yield was 89.2%.
The nmr data were the same as in example 1.
Examples 5 to 32
The yield of the product obtained by replacing copper iodide (CuI) as the catalyst of examples 1 to 4 with the same molar amount of another copper compound according to the correspondence shown in table 1 and the other operations were the same as shown in table 1.
TABLE 1 product yields on different catalysts
It can be seen that the kind of catalyst has a significant influence on the product yield, wherein cuprous iodide (CuI) or cuprous chloride (CuCl) has better catalytic effect, while cuprous iodide (CuI) has the best catalytic performance, the catalytic effect of the monovalent copper source is generally better than that of the divalent copper source, and the yield of the catalytic reaction of the divalent copper source is reduced to 52.3-56.5% or even lower.
Examples 33 to 40
According to the corresponding relation shown in table 2, the ligand triethylamine in examples 1-4 is replaced by other ligands with the same molar weight, and other operations are different, and the product yield is shown in table 2.
TABLE 2 product yields under different ligands
It can be seen that triethylamine, n-tributylamine and tri-tert-butylamine have suitable coordination among all ligands, while the yield of other ligands is significantly reduced or even no product can be obtained. In addition, other 1, 10-phenanthroline (Phen) with strong coordination property and the like are more remarkably reduced or even not reacted.
From the above, it is clear from all the examples that when the method of the present invention is used, the compounds of formulae (II), (III) and triethylamine can be smoothly reacted to obtain the desired product, and the yield is good, the post-treatment is simple, and the effects are obtained depending on the combined synergistic effect of a plurality of factors such as the catalyst and the ligand.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
Claims (8)
1. A method for preparing a chromone derivative, comprising: the method comprises the following steps:
in the presence of a copper compound, reacting an o-hydroxybenzoyl acetylene compound shown as a formula (II) and a diazo compound shown as a formula (III) to obtain the chromone derivative shown as a formula (I),
the R is1、R2Independently selected from H, cyano, nitro, hydroxy, phenyl, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl or halo C1-C6Any one of alkoxy groups; the copper compound comprises any one or more of copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, cuprous iodide, cuprous bromide, cuprous chloride, cuprous thiophene-2-formate and cuprous acetate; the reaction is carried out in the presence of a ligand comprising N, N-dimethylformamide, triethylamine, N-tributylamine, tri-tert-butylamine, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine]Any one or more of amines.
2. The method of claim 1, wherein: the R is2Is C1-C6An alkoxy group.
3. The method of claim 1, wherein: the reaction is carried out in an organic solvent, and the organic solvent comprises any one or more of N, N-dimethylformamide, N-dimethylacetamide, dichloromethane, chlorobenzene, benzene, xylene, dimethyl sulfoxide and N-methylpyrrolidone.
4. The method of claim 1, wherein: the molar ratio of the o-hydroxybenzoyl acetylene compound to the copper compound is 1: 0.05-0.2.
5. The method of claim 1, wherein: the mol ratio of the o-hydroxybenzoyl acetylene compound to the ligand is 1: 0.1-2.
6. The method of claim 1, wherein: the mol ratio of the o-hydroxybenzoyl acetylene compound to the diazo compound is 1: 1-3.
7. The method according to claim 3, wherein: the ratio of the o-hydroxybenzoyl acetylene compound to the organic solvent is 1mmol:5-15 mL.
8. The method of claim 1, wherein: the temperature of the reaction is 25-80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110380660.7A CN113214205B (en) | 2021-04-09 | 2021-04-09 | Preparation method of chromone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110380660.7A CN113214205B (en) | 2021-04-09 | 2021-04-09 | Preparation method of chromone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113214205A CN113214205A (en) | 2021-08-06 |
| CN113214205B true CN113214205B (en) | 2022-06-10 |
Family
ID=77086735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110380660.7A Active CN113214205B (en) | 2021-04-09 | 2021-04-09 | Preparation method of chromone derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113214205B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102421767A (en) * | 2009-03-10 | 2012-04-18 | 武田药品工业株式会社 | Benzofuran derivatives |
| CN110551136A (en) * | 2019-09-16 | 2019-12-10 | 贵州大学 | preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6756403B2 (en) * | 2000-06-02 | 2004-06-29 | Eli Lilly And Company | Methods for producing chiral chromones, chromanes, amino substituted chromanes and intermediates therefor |
-
2021
- 2021-04-09 CN CN202110380660.7A patent/CN113214205B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102421767A (en) * | 2009-03-10 | 2012-04-18 | 武田药品工业株式会社 | Benzofuran derivatives |
| CN110551136A (en) * | 2019-09-16 | 2019-12-10 | 贵州大学 | preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene |
Non-Patent Citations (1)
| Title |
|---|
| Product Class4:Benzopyranones and Benzopyranthiones;A.C.Williams and N.Camp;《Science of Synthesis》;20031231;第14卷;第347-638页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113214205A (en) | 2021-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113045489B (en) | Preparation method of 3-arylquinoline-2 (1H) ketone derivative | |
| CN113307790B (en) | Preparation method of 3-quinolyl-5-trifluoromethyl substituted 1,2, 4-triazole compound | |
| CN110204486B (en) | Synthesis method of quinoline derivative | |
| CN109232363B (en) | Synthetic method of 3-selenocyanoindole compound | |
| CN110183378B (en) | Nicotinamide derivative and catalytic synthesis method thereof | |
| CN114478375B (en) | Preparation method of 3-alkenyl quinoline-2 (1H) ketone derivative | |
| CN114195711B (en) | Preparation method of quinoline-4 (1H) -ketone compound | |
| CN112500339B (en) | Synthesis method of 8-acylquinoline derivative | |
| CN114539198A (en) | Preparation method of amide compound containing (iso) chroman structure | |
| CN113214205B (en) | Preparation method of chromone derivative | |
| CN111423351B (en) | Chiral copper compound and preparation method and application thereof | |
| CN108864164B (en) | Synthesis method of primary amine-guided 2-alkynyl indole compound | |
| CN112094220B (en) | Green synthesis method of 3-sulfone methyl-1H-indole compound | |
| CN113234015B (en) | 3-acyl dihydroquinoline derivative and preparation method and application thereof | |
| CN113214162A (en) | Preparation method of benzimidazole derivative | |
| CN110294725B (en) | Derivative of sponge furanone and catalytic synthesis method thereof | |
| CN113402476A (en) | Imine oxazine derivative and preparation method thereof | |
| CN112552242B (en) | Method for synthesizing cinnoline salt compound | |
| JP2017132738A (en) | Manufacturing method of bipyridyl compound | |
| CN112442005B (en) | N-sulfonyl imine coumarin derivative and preparation method thereof | |
| CN108250103B (en) | Synthetic method of pharmaceutical intermediate diarylethene compound | |
| CN112239456B (en) | Preparation method of substituted 2, 3-dihydroquinolone compound | |
| CN114315734B (en) | Benzimidazole derivative and synthesis method thereof | |
| CN112321554A (en) | Genistein structure modified derivative and synthesis method thereof | |
| CN112209866B (en) | Method for preparing 1-tertiary butyl-3, 3-dimethyl indoline compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |