CN111995605A - Chrysin cinnamate or its derivative and its preparation method - Google Patents
Chrysin cinnamate or its derivative and its preparation method Download PDFInfo
- Publication number
- CN111995605A CN111995605A CN202010891873.1A CN202010891873A CN111995605A CN 111995605 A CN111995605 A CN 111995605A CN 202010891873 A CN202010891873 A CN 202010891873A CN 111995605 A CN111995605 A CN 111995605A
- Authority
- CN
- China
- Prior art keywords
- chrysin
- cinnamate
- compound
- catalyst
- reaction
- 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.)
- Granted
Links
Images
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
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses chrysin cinnamate or a derivative thereof and a preparation method thereof, belonging to the field of organic synthesis. The invention carries out Steglich esterification reaction on chrysin and cinnamic acid or derivatives thereof in an organic solvent under the action of a condensing agent and a catalyst to prepare the chrysin cinnamate or the derivatives thereof, has simple method, easy industrial production and high yield of target products of more than 40 percent, and the obtained chrysin cinnamate or the derivatives thereof have the characteristics of chrysin and cinnamic acid or the derivatives thereof, thereby providing a compound source for biological activity screening.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to chrysin cinnamate or a derivative thereof and a preparation method thereof.
Background
The synthesis of new molecules with potential biological activity by reacting two or more molecules with biological activity is an important strategy for constructing new compounds[1-2]. Chrysin is a natural polyphenol flavone compound with wide pharmacological activity extracted from oroxylum indicum of purple Weividae[3]It is widely found in honey and beeswax, and has antioxidant effectMultiple biological activities of dissolving, resisting virus, reducing blood sugar, resisting anxiety, etc[4-8]However, it also has the disadvantages of low solubility and poor bioavailability[8-9]. Cinnamic acid is a compound extracted from cortex Cinnamomi[10]The derivative of the compound has various biological activities of oxidation resistance, tumor resistance, bacteriostasis and the like[11-14]The research finds that the biological activity of various cinnamic acid derivatives is higher than that of the prototype drug[15]. Therefore, a series of novel compounds with diversity characteristics are synthesized by reacting chrysin and cinnamic acid derivatives, and a compound source is provided for biological activity screening.
Disclosure of Invention
In order to solve the defects and shortcomings of the prior art, the invention aims to provide chrysin cinnamate or derivatives thereof and a preparation method thereof.
In order to achieve the above objects, in a first aspect, the present invention provides a method for preparing chrysin cinnamate or a derivative thereof, comprising the steps of: performing Steglich esterification reaction on chrysin (with a structure shown in a formula (1)) and a compound shown in a structural formula (2) in an organic solvent under the action of a condensing agent and a catalyst to obtain chrysin cinnamate or a derivative thereof, wherein the structural formula of the chrysin cinnamate or the derivative thereof is shown in a formula (3);
each R is independently halogen, nitro, straight or branched chain alkyl, or straight or branched chain alkoxy, or two adjacent R are linked together to form-O (CH)2)pO-; n is an integer of 0 to 5; p is an integer of 1 or more.
The preparation method can prepare the chrysin cinnamate or the derivative thereof through a one-step method, not only has simple method and high yield of the target product of more than 40 percent, is easy for industrial production, but also has the characteristics of chrysin and cinnamic acid or the derivative thereof, and provides a compound source for bioactive screening.
As a preferred embodiment of the production method of the present invention, said n is 0, 1 or 2.
As a preferred embodiment of the preparation method of the present invention, said n is 1, and said R is 2-CH3-、3-CH3-、4-CH3-、2-Cl、3-Cl、4-Cl、2-Br、3-Br、4-Br、2-F、3-F、4-F、2-NO2-、3-NO2-、4-NO2-、2-OCH3、3-OCH3Or 4-OCH3(ii) a Or n is 2, two R are same and are respectively halogen, nitro, linear or branched alkyl or linear or branched alkoxy, or two R are adjacent and are connected together to form-O- (CH)2)p-O-。
As a preferred embodiment of the preparation method of the invention, n is 2, and two R are the same and are respectively 3-OCH3And 4-OCH3Or two R are adjacent and linked together to form 3,4 (O-CH)2-O)。
As a preferred embodiment of the preparation method of the present invention, the condensing agent is 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (i.e., EDCI) and the catalyst is 4-dimethylaminopyridine (i.e., DMAP). When EDCI is used as a condensing agent and DMAP is used as a catalyst, the obtained target product has high yield and is easier to purify.
As a preferred embodiment of the preparation method of the present invention, the reaction temperature of the Steglich esterification reaction is 0 to 45 ℃ and the reaction time is 4 to 24 hours, and the molar ratio of the chrysin, the compound represented by the structural formula (2), the condensing agent and the catalyst is chrysin: a compound represented by structural formula (2): condensing agent: catalyst 1:1.5:1.5: 0.5.
In a preferred embodiment of the preparation method of the present invention, the reaction temperature of the Steglich esterification reaction is normal temperature, the reaction time is 6 hours, and the molar ratio of the chrysin, the compound represented by the structural formula (2), the condensing agent and the catalyst is chrysin: a compound represented by structural formula (2): condensing agent: catalyst 1:1.5:1.5: 0.5.
As a preferred embodiment of the preparation method of the invention, the Steglich esterification reaction is carried out under the protection of protective gas.
As a preferred embodiment of the preparation method of the present invention, the preparation method further comprises the steps of: and (3) carrying out solid-liquid separation on the system after the Steglich esterification reaction, collecting the solid, and washing the solid by using petroleum ether, ethyl acetate and acetone in sequence. After being washed by petroleum ether, ethyl acetate and acetone in sequence, impurities can be removed, and a pure target product is obtained.
As a preferred embodiment of the preparation method of the present invention, the preparation method further comprises the steps of: after the washing, a drying treatment is performed.
In a second aspect, the present invention provides chrysin cinnamate or a derivative thereof prepared by the above preparation method.
Compared with the prior art, the invention has the following advantages: the chrysin cinnamate or the derivative thereof is prepared from chrysin and cinnamic acid or the derivative thereof through a one-step method, the method is simple, the industrial production is easy, the yield of the target product is high and is more than 40%, and the obtained chrysin cinnamate or the derivative thereof has the characteristics of chrysin and cinnamic acid or the derivative thereof, so that a compound source is provided for biological activity screening.
Drawings
FIG. 1 is a reaction scheme for each example (starting material 2a corresponds to product 3a, starting material 2b corresponds to product 3c … …, and so on, starting material 2n corresponds to product 3 n);
figure 2 is the reaction mechanism of chrysin and cinnamic acid of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
The reagents used in the following examples were all analytical grade, and the apparatus used was an OptiMelt MPA100 melting point apparatus (SRS); bruker 500MHz NMR spectrometer (BRUKER, Germany, DMSO-d6 as solvent, TMS as internal standard); thermo Fisher LCQ fly model liquid chromatography-mass spectrometer (Thermo Fisher Seientific, USA).
Example 1
A50 mL round-bottom flask was charged with chrysin (compound of formula (1)) (1mmol,1eq), cinnamic acid (compound of formula (2 a)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in that order, and then placed under N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3a (chrysin cinnamate).
Example 2
A50 mL round-bottomed flask was charged with chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 b)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (3), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 b.
Example 3
In a 50mL round-bottom flask were added chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 c)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 c.
Example 4
In a 50mL round-bottom flask were added chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 d)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 d.
Example 5
A50 mL round-bottomed flask was charged with chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 e)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 e.
Example 6
To a 50mL round-bottomed flask were added chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 f)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0) in this order.5mmol,0.5eq) and then in N2Under the protection of (3), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 f.
Example 7
A50 mL round-bottomed flask was charged with chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 g)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain 3g of a compound.
The compound obtained 3 g: light yellow solid, yield 88.7%, m.p.234.6-237.2 ℃;1H NMR(500MHz,DMSO-d6):12.90(s,1H),8.15(d,J＝7.2Hz,2H),7.97–7.87(m,3H),7.64(dq,J＝14.6,7.1Hz,3H),7.56(d,J＝8.6Hz,2H),7.23(d,J＝2.1Hz,1H),7.20(s,1H),6.98(d,J＝16.0Hz,1H),6.79(d,J＝2.1Hz,1H)；LC-MS(ESI)m/z:C24H16ClO5{[M+H]+calculated value 419.06, actual value 419.07.
Example 8
Adding chrysin (compound shown in formula (1)) (1mmol,1eq) and cinnamic acid (structure) into a 50mL round-bottom flask in sequenceCompound of formula (2h) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq.) and DMAP (0.5mmol,0.5 eq.) followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain the compound for 3 h.
Example 9
A50 mL round-bottomed flask was charged with chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 i)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 i.
The compound 3i obtained: a light yellow solid, with a yield of 43.4%, m.p.184.7-186.3 ℃;1H NMR(500MHz,DMSO-d6):12.89(s,1H),8.15(d,J＝7.2Hz,2H),7.93(d,J＝16.0Hz,1H),7.79(dt,J＝10.1,2.1Hz,1H),7.72～7.58(m,4H),7.56～7.48(m,1H),7.33(td,J＝8.6,2.3Hz,1H),7.24(d,J＝2.0Hz,1H),7.20(s,1H),7.03(d,J＝16.1Hz,1H),6.80(d,J＝2.1Hz,1H)；13C NMR(125MHz,DMSO-d6):183.15,164.73,164.45,161.31,156.86,156.32,146.39,136.76,132.94,131.55,131.48,130.88,129.71,127.16,125.85,118.77,115.46,115.28,108.86,106.29,105.94,102.26；LC-MS(ESI)m/z:C24H15FNaO5{[M+Na]+calculated value 425.07, actual value 425.08.
Example 10
Adding chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 j)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in sequence into a 50mL round-bottomed flask, and adding the mixture into a flask2Under the protection of (3), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 j.
The compound 3j obtained: yellow solid, yield 72.5%, m.p.247.7-251.1 ℃;1H NMR(500MHz,DMSO-d6):12.90(s,1H),8.30(d,J＝8.8Hz,2H),8.19～8.09(m,4H),8.05(d,J＝16.0Hz,1H),7.69～7.58(m,3H),7.25(d,J＝2.1Hz,1H),7.19(d,J＝7.8Hz,1H),7.15(s,1H),6.82(d,J＝2.0Hz,1H)；13C NMR(125MHz,DMSO-d6):183.19,164.75,164.14,161.33,156.86,156.22,148.91,145.02,140.55,132.96,130.87,130.37,129.72,127.16,124.53,121.50,108.92,106.31,105.91,102.24；LC-MS(ESI)m/z:C24H15NKO7{[M+K]+calculated value 468.05, actual value 468.20.
Example 11
A50 mL round-bottom flask was charged with chrysin (compound of formula (1)) (1mmol,1eq), cinnamic acid (compound of formula (2 k)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in that order, and then placed under N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 k.
Compound 3k obtained: light yellow solid, yield 89.9%, m.p.169.2-172.5 ℃;1H NMR(500MHz,DMSO-d6):12.88(s,1H),8.15(d,J＝7.1Hz,2H),8.10(d,J＝16.1Hz,1H),7.84(dd,J＝7.8,1.7Hz,1H),7.69～7.58(m,3H),7.49(td,J＝8.1,7.6,1.6Hz,1H),7.22(d,J＝2.1Hz,1H),7.19(s,1H),7.16(d,J＝8.2Hz,1H),7.05(t,J＝7.5Hz,1H),6.91(d,J＝16.1Hz,1H),6.78(d,J＝2.1Hz,1H),3.91(s,3H)；13C NMR(125MHz,DMSO-d6):183.15,164.96,164.70,161.28,158.74,156.85,156.48,142.57,132.94,129.82,129.71,127.16,122.33,121.33,117.06,112.41,106.26,105.99,102.29,56.25；LC-MS(ESI)m/z:C25H18KO6{[M+K]+calculated value 453.07, actual value 453.19.
Example 12
A50 mL round-bottomed flask was charged with chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 l)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain 3l of a compound.
The compound 3l obtained: yellow solid, yield 73.4%, m.p.218.5-221.1 ℃;1H NMR(500MHz,DMSO-d6):12.88(s,1H),8.17～8.13(m,2H),7.88(d,J＝15.9Hz,1H),7.81(d,J＝8.8Hz,2H),7.67～7.59(m,3H),7.21(d,J＝2.0Hz,1H),7.19(s,1H),7.03(d,J＝8.7Hz,2H),6.81～6.75(m,2H),3.82(s,3H),3.83(s,3H)；13C NMR(125MHz,DMSO-d6):183.09,164.89,164.69,161.26,157.84,156.84,156.53,147.76,132.94,131.27,130.89,129.71,127.15,115.00,114.14,108.73,106.25,105.96,102.27,55.90；LC-MS(ESI)m/z:C25H19O6{[M+H]+calculated value 415.17, actual value 415.10.
Example 13
A50 mL round-bottomed flask was charged with chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 m)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in this order, followed by N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 m.
The resulting compound3 m: yellow solid, yield 74.4%, m.p.172.3-174.5 ℃;1H NMR(500MHz,DMSO-d6):12.88(s,1H),8.14(d,J＝7.2Hz,2H),7.85(d,J＝15.9Hz,1H),7.70～7.57(m,3H),7.48(d,J＝2.1Hz,1H),7.37(dd,J＝8.4,2.0Hz,1H),7.21(d,J＝2.1Hz,1H),7.19(s,1H),7.03(d,J＝8.4Hz,1H),6.85(d,J＝16.0Hz,1H),6.76(d,J＝2.0Hz,1H),3.83(d,J＝6.6Hz,6H)；13C NMR(125MHz,DMSO-d6):183.14,164.93,164.67,161.26,156.83,156.56,152.03,149.49,148.18,132.93,130.87,129.70,127.15,127.03,124.35,114.29,111.95,111.00,108.71,106.23,105.92,102.24,56.13,56.08；LC-MS(ESI)m/z:C26H20NaO7{[M+Na]+calculated value 467.11, actual value 467.10.
Example 14
A50 mL round-bottom flask was charged with chrysin (compound of formula (1)) (1mmol,1eq), cinnamic acid (compound of formula (2N)) (1.5mmol,1.5eq.), EDCI (1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) in that order, and then charged with N2Under the protection of (1), adding dichloromethane (10.0mL), reacting at normal temperature for about 6h (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3 n.
The compound 3n obtained: yellow solid, yield 90.6%, m.p.220.2-221.4 ℃;1H NMR(500MHz,DMSO-d6):12.88(s,1H),8.18～8.11(m,2H),7.84(d,J＝15.9Hz,1H),7.68～7.57(m,3H),7.55(d,J＝1.7Hz,1H),7.32(dd,J＝8.2,1.7Hz,1H),7.21(d,J＝2.1Hz,1H),7.18(s,1H),7.01(d,J＝8.0Hz,1H),6.79(d,J＝15.9Hz,1H),6.76(d,J＝2.0Hz,1H),6.12(s,2H)；13C NMR(125MHz,DMSO-d6):183.14,164.86,164.69,161.26,156.84,156.52,150.45,148.65,147.82,132.94,130.87,129.71,128.68,127.15,126.49,114.71,109.07,108.74,107.39,106.24,105.97,102.27；LC-MS(ESI)m/z:C25H17O7{[M+H]+calculated value 429.10, actual value 429.10.
Comparative example 1
Adding chrysin (compound shown in formula (1)) (1mmol,1eq) and cinnamic acid (shown in formula (2 a)) in a 50mL round-bottom flask in sequenceCompound) (1.5mmol,1.5eq.), then in N2Under the protection of (3), dichloromethane (10.0mL) was added and the reaction was carried out at room temperature for about 6 hours (TLC detection), and it was found that the reaction did not proceed and the target compound 3a could not be obtained.
Comparative example 2
In a 50mL round-bottom flask, chrysin (compound represented by formula (1)) (1mmol,1eq), cinnamic acid (compound represented by formula (2 a)) (1.5mmol,1.5eq.), DCC (N, N' -dicyclohexylcarbodiimide, 1.5mmol,1.5eq) and DMAP (0.5mmol,0.5eq) were added in this order, followed by addition of N2Under the protection of (3), adding dichloromethane (10.0mL), reacting at normal temperature for about 8h (TLC detection), after the reaction is finished, carrying out suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain a compound 3a, wherein the yield is 84.6%, but the obtained compound 3a still contains impurities.
Comparative example 3
Adding dichloromethane (10.0mL), cinnamic acid (compound shown in structural formula (2 a)) (1.5mmol,1.5eq.) and thionyl chloride (1.5mmol,1.5eq.) into a 50mL round-bottom flask in sequence, reacting at room temperature for about 8 hours, concentrating to remove the solvent, dissolving in dichloromethane (10.0mL) again, adding chrysin (compound shown in structural formula (1)) (1mmol,1 eq.) into the system, reacting at room temperature for about 8 hours (TLC detection), after the reaction is finished, performing suction filtration, washing a filter cake by using petroleum ether, ethyl acetate and acetone in sequence, and drying to obtain the compound 3a with the yield of 86.5%.
Comparing example 1 with comparative examples 1-3, it can be seen that the reaction does not proceed when no additional catalyst reagent is added; under the action of EDCI and DMAP, the reaction can be completed within 6h, the yield reaches 95.1%, and the obtained product is washed by petroleum ether, ethyl acetate and acetone in sequence to achieve purity; under the action of DCC and DMAP, the reaction time is longer, the yield is obviously reduced, and the purification difficulty of the obtained product is higher; using SOCl2Acylation of cinnamic acid followed by esterification with chrysin requires less reaction time, but requires two steps, with slightly lower yields and more stringent reaction conditions, so it is most appropriate to select conditions using EDCI and DMAP for carrying out the reaction.
The experimental results and literature reports baseOn the basis of[16-18]The inventors speculate that a possible reaction mechanism (see figure 2) is that first cinnamic acid reacts with EDCI to form a more reactive O-acylisourea, and then the hydroxyl group at C-7 of chrysin attacks the O-acylisourea to form the corresponding ester and EDCI by-products. At the same time, in order to prevent 1, 3-rearrangement of O-acylisourea in the reaction, the acyl transfer reagent DMAP was added to reduce the formation of by-products.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Reference to the literature
[1]MOHR J T,KROUT M R,STOLTZ B M.Natural products as inspiration for the development of asymmetric catalysis[J].Nature,2008,455(7211):323-332.
[2]MAYER S,KEGLEVICH P,
-BALOGH P,et al.Synthesis and In Vitro Anticancer Evaluation of Novel Chrysin and 7-Aminochrysin Derivatives[J].Molecules,2020,25(4):888.
[3]DHAWAN K,KUMAR S,SHARMA A.Beneficial effects of chrysin and benzoflavone on virility in 2-year-old male rats[J].Journal of Medicinal Food,2002,5(1):43-48.
[4]KIM D C,RHO S H,SHIN J C,et al.Inhibition of melanogenesis by 5,7-dihydroxyflavone(chrysin)via blocking adenylyl cyclase activity[J].Biochemical and biophysical research communications,2011,411(1):121-125.
[5]KAMAL A,MURTY J,VISWANATH A,et al.Synthesis,biological evaluation of 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone,5-carboethoxymethyl-4′,7-dihydroxyflavone and their analogues[J].Bioorganic&medicinal chemistry letters,2012,22(14):4891-4895.
[6]MANI R,NATESAN V.Chrysin:Sources,beneficial pharmacological activities,and molecular mechanism of action[J].Phytochemistry,2018,145:187-196.
[7]TSUJI P A,WINN R N,WALLE T.Accumulation and metabolism of the anticancer flavonoid 5,7-dimethoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish[J].Chemico-biological interactions,2006,164(1-2):85-92.
[8]KASALA E R,BODDULURU L N,MADANA R M,et al.Chemopreventive and therapeutic potential of chrysin in cancer:mechanistic perspectives[J].Toxicology letters,2015,233(2):214-225.
[9] Development of Chrysage, Zhang Yi, Saxifraga, et al chrysin preparation [ J ]. Chinese Pharmacist,2018,21(4):714-717 (QU Y, ZHANG Y, XIONG T, et al. research progress in the preparation of chrysin [ J ]. China Pharmacist,2018,21(4): 714-717)
[10] Application of new synthesis method of cinnamic acid and its derivatives [ J ] application chemical industry, 2015,44(03):442 + 444+449.
(CHU C S,WANG X L,HU Y T,et al.Research on a new method for the synthesis of cinnamic acid and its derivatives[J].Applied Chemical Industry,2015,44(03):442-444+449.)
[11]WEI Q Y,JIANG H,ZHANG J X,et al.Synthesis of N-hydroxycinnamoyl amino acid ester analogues and their free radical scavenging and antioxidative activities[J].Medicinal Chemistry Research,2012,21(8):1905-1911.
[12]DENG X Q,WU D,WEI C X,et al.Synthesis and antidepressant-like action of N-(2-hydroxyethyl)cinnamamide derivatives in mice[J].Medicinal Chemistry Research,2011,20(8):1273-1279.
[13]KUJUR A,KIRAN S,DUBEY N K,et al.Microencapsulation of Gaultheria procumbens essential oil using chitosan-cinnamic acid microgel:Improvement of antimicrobial activity,stability and mode of action[J].LWT,2017,86:132-138.
[14]GARCIA-JIMENEZ A,
-MOLINA F,TERUEL-PUCHE J A,et al.Catalysis and inhibition of tyrosinase in the presence of cinnamic acid and some of its derivatives[J].International journal of biological macromolecules,2018,119:548-554.
[15] Application and development of Jianweihua, Bengqi, cinnamic acid and its derivatives [ J ] spice and essence cosmetics, 2012,10(5):53-54.
(JIANG W H,MENG Q.Application and Development on Cinnamic Acid and its Derivatives[J].Flavour Fragrance Cosmetics,2012,10(5):53-54.)
[16]BABU S A.EDC/DMAP-mediated direct condensation of dicarboxylic acids and diols:A concise synthesis of extra large polyether macrocyclic lactones and their X-ray structures[J].Tetrahedron Letters,2016,57(51):5801-5807.
[17]MCCOURT R O,SCANLAN E M.A Sequential Acyl Thiol–Ene and Thiolactonization Approach for the Synthesis of-Thiolactones[J].Organic letters,2019,21(9):3460-3464.
[18] Zealan, Wangpuhai, Sun Li, et al reaction of 7-ethylcamptothecin with acetylsalicylic acid in the presence of EDCI/DMAP [ J ] chemical research and use, 2016,28(02), 214-.
(CAI R,WANG P H,SUN L.Studies on esterification reaction of 7-ethylcamptothecin and acetylsalicylic acid in presence of EDCI/DMAP[J].Chemical Research and Application,2016,28(02),214-217).
Claims (10)
1. A preparation method of chrysin cinnamate or derivatives thereof is characterized by comprising the following steps: performing Steglich esterification reaction on chrysin and a compound shown in a structural formula (2) in an organic solvent under the action of a condensing agent and a catalyst to obtain chrysin cinnamate or a derivative thereof, wherein the structural formula of the chrysin cinnamate or the derivative thereof is shown in a formula (3);
each R is independently halogen, nitro, straight or branched chain alkyl, or straight or branched chain alkoxy, or two adjacent R are linked together to form-O (CH)2)pO-; n is an integer of 0 to 5; p is an integer of 1 or more.
2. The method according to claim 1, wherein n is 0, 1 or 2.
3. The method according to claim 2, wherein n is 1 and R is 2-CH3-、3-CH3-、4-CH3-、2-Cl、3-Cl、4-Cl、2-Br、3-Br、4-Br、2-F、3-F、4-F、2-NO2-、3-NO2-、4-NO2-、2-OCH3、3-OCH3Or 4-OCH3(ii) a Or n is 2, two R are same and are respectively halogen, nitro, linear or branched alkyl or linear or branched alkoxy, or two R are adjacent and are connected together to form-O- (CH)2)p-O-。
4. The method according to claim 3, wherein n is 2, and R's are the same and each is 3-OCH3And 4-OCH3Or two R are adjacent and linked together to form 3,4 (O-CH)2-O)。
5. The method according to claim 1, wherein the condensing agent is 1-ethyl-3 (3-dimethylpropylamine) carbodiimide and the catalyst is 4-dimethylaminopyridine.
6. The method as claimed in claim 1, wherein the reaction temperature of the Steglich esterification reaction is 0-45 ℃ and the reaction time is 4-24 hours, and the molar ratio of the chrysin, the compound represented by the structural formula (2), the condensing agent and the catalyst is chrysin: a compound represented by structural formula (2): condensing agent: catalyst 1:1.5:1.5: 0.5.
7. The method as claimed in claim 6, wherein the Steglich esterification reaction is carried out at normal temperature for 6 hours, and the molar ratio of chrysin, the compound represented by the structural formula (2), the condensing agent and the catalyst is chrysin: a compound represented by structural formula (2): condensing agent: catalyst 1:1.5:1.5: 0.5.
8. The process of claim 1, wherein the Steglich esterification reaction is carried out under protective gas.
9. The method of claim 1, further comprising the steps of: and (3) carrying out solid-liquid separation on the system after the Steglich esterification reaction, collecting the solid, washing the solid by using petroleum ether, ethyl acetate and acetone in sequence, and then drying.
10. Chrysin cinnamate or a derivative thereof obtainable by a process according to any one of claims 1 to 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010891873.1A CN111995605B (en) | 2020-08-28 | 2020-08-28 | Chrysin cinnamate or its derivative and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010891873.1A CN111995605B (en) | 2020-08-28 | 2020-08-28 | Chrysin cinnamate or its derivative and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111995605A true CN111995605A (en) | 2020-11-27 |
| CN111995605B CN111995605B (en) | 2023-02-17 |
Family
ID=73464740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010891873.1A Active CN111995605B (en) | 2020-08-28 | 2020-08-28 | Chrysin cinnamate or its derivative and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111995605B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114874124A (en) * | 2022-05-12 | 2022-08-09 | 五邑大学 | Melatonin cinnamic acid derivative and preparation method thereof |
-
2020
- 2020-08-28 CN CN202010891873.1A patent/CN111995605B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| IN SIK KIM ET AL.,: "Effect of (E)-2-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-7-yl-3-(3,4-dimethoxyphenyl) acrylate on the development of atopic dermatitis-like lesions", 《LIFE SCIENCES》 * |
| JOON-SU SHIN ET AL.,: "SYNTHESIS AND HYPOGLYCEMIC EFFECT OF CHRYSIN DERIVATIVES", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| K.SURESH BABU ET AL.,: "Synthesis and in vitro study of novel 7-O-acyl derivatives of Oroxylin A as antibacterial agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| TOMOHIRO ITOH ET AL.,: "Inhibitory effects of flavonoids isolated from Fragaria ananassa Duch on IgE-mediated degranulation in rat basophilic leukemia RBL-2H3", 《BIOORG.MED.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114874124A (en) * | 2022-05-12 | 2022-08-09 | 五邑大学 | Melatonin cinnamic acid derivative and preparation method thereof |
| CN114874124B (en) * | 2022-05-12 | 2023-07-04 | 五邑大学 | Melatonin cinnamic acid derivative and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111995605B (en) | 2023-02-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Practical synthesis of naringenin | |
| Devakaram et al. | Synthesis and antimalarial evaluation of novel benzopyrano [4, 3-b] benzopyran derivatives | |
| EP2468741A1 (en) | Novel quercetin derivatives, their preparation, pharmaceutical compositions containing them and their use | |
| Kaneria et al. | Microwave assisted synthesis and biological activity of 3-aryl-furo [3, 2-c] coumarins | |
| CN111995605B (en) | Chrysin cinnamate or its derivative and its preparation method | |
| CN103145583B (en) | Raceme alkannin naphthazarin parent nucleus hydroxyl methylation carbonyl oxime derivative and preparation and application thereof | |
| KR101119027B1 (en) | Method for preparating ascorbic acid derivatives | |
| KR100346672B1 (en) | Method for preparing 3-O-substituted ascorbic acid | |
| CN107759551B (en) | Method for synthesizing scutellarin aglycone | |
| CN110845466B (en) | Oxacyclonadiene derivatives, pharmaceutical compositions thereof, process for their preparation and their use | |
| CN103130680B (en) | High-optical-purity alkannin and Akannin naphthazarin nuclear parent hydroxyl methylation carbonyl oxime derivative and preparation method and application thereof | |
| CN105849093A (en) | A crystalline anhydrous form of cabazitaxel, process for the preparation and pharmaceutical compositions thereof | |
| CN104672136B (en) | 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof | |
| CN110183371B (en) | Preparation process of zafirlukast intermediate | |
| WO2009049493A1 (en) | Preparation of seselin and its derivatives | |
| US6191279B1 (en) | Dipyrano-quinolinones useful as anti viral agents and a process for preparing the same | |
| Cui et al. | A novel synthesis of naringenin and related flavanones | |
| EP3002276B1 (en) | Shikonin, alkannin, and racemic parent nucleus carbonyl oxime derivatives and applications thereof | |
| CN115197236B (en) | Linear type glabra A analogue and preparation and application thereof | |
| CN110105316B (en) | Resveratrol-phthalide hybrid compound and preparation method and application thereof | |
| CN114702506B (en) | 11-carbonyl-20-ethoxy source oridonin and 14-OH esterified serial derivatives and application thereof | |
| CN110669031B (en) | Total synthesis method of natural product isoperidone J | |
| EP3733656B1 (en) | Method for synthesis of lobaric acid and analog thereof | |
| CN112062743B (en) | Resveratrol derivative and application thereof | |
| CN105481814A (en) | Synthetic method for isorhamnetin |
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 |