CN111995605B - Chrysin cinnamate or its derivative and its preparation method - Google Patents

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, and the method is simple, easy for industrial production and high in yield of target products of more than 40 percent.

Description

Chrysin cinnamate or derivatives thereof and preparation method thereof

technical field

The invention belongs to the field of organic synthesis, and in particular relates to a chrysin cinnamate or a derivative thereof and a preparation method thereof.

Background technique

It is an important strategy to construct new compounds by reacting two or more molecules with biological activity to synthesize new molecules with potential biological activity ^[1-2] . Chrysin is a natural polyphenolic flavonoid compound with a wide range of pharmacological activities, which is extracted from the Violaceae plant Arborinae ^[3] . It is widely found in honey and beeswax, and has antioxidant, antiviral, hypoglycemic, Anti-anxiety and other biological activities ^[4-8] , but it also has disadvantages such as low solubility and poor bioavailability ^[8-9] . Cinnamic acid is a compound extracted from traditional Chinese medicine cinnamon bark ^[10] , and its derivatives are widely found in nature, and have various biological activities such as anti-oxidation, anti-tumor, and antibacterial ^[11-14] . Studies have found that, The biological activities of various cinnamic acid derivatives are higher than those of their prototype drugs ^[15] . Therefore, by reacting chrysin and cinnamic acid derivatives to synthesize a series of new compounds with diverse characteristics, it will provide a source of compounds for biological activity screening.

Contents of the invention

In order to solve the shortcomings and deficiencies in the above-mentioned prior art, the object of the present invention is to provide a kind of chrysin cinnamate or derivatives thereof and a preparation method thereof.

In order to achieve the above object, the first aspect, the present invention provides a kind of preparation method of chrysin cinnamate or derivative thereof, it comprises the following steps: combine chrysin (structure as shown in formula (1)) and structural formula (2 ) under the action of a condensing agent and a catalyst to undergo a Steglich esterification reaction in an organic solvent to obtain the chrysin cinnamate or a derivative thereof, and the structural formula of the chrysin cinnamate or a derivative thereof is as Shown in formula (3);

Each R is independently halogen, nitro, straight-chain or branched-chain alkyl, or straight-chain or branched-chain alkoxy, or two adjacent Rs are linked together to form -O(CH ₂ ) _p O-; n is An integer of 0 to 5; p is an integer of 1 or more.

The above-mentioned preparation method can obtain chrysin cinnamate or its derivatives through a one-step method. Not only is the method simple, it is easy for industrial production, and the yield of the target product is high, above 40%, and the obtained chrysin cinnamate or its derivatives have The characteristics of chrysin and cinnamic acid or its derivatives provide a source of compounds for biological activity screening.

As a preferred embodiment of the preparation method of the present invention, the 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-CH ₃ -, 3-CH ₃ -, 4-CH ₃ -, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-F, 3-F, 4-F, 2-NO ₂ -, 3-NO ₂ -, 4-NO ₂ -, 2-OCH ₃ , 3-OCH ₃ or 4-OCH ₃ ; or the n is 2, and the two Rs are the same and are respectively halogen, nitro, straight-chain or branched-chain alkyl, or straight-chain or branched-chain alkoxy, or two Rs are adjacent and link together to form -O-(CH ₂ ) _p -O-.

As a preferred embodiment of the preparation method of the present invention, the n is 2, the two Rs are the same and are respectively 3-OCH ₃ and 4-OCH ₃ , or the two Rs are adjacent and connected together to form 3,4(O- _CH2 -O).

As a preferred embodiment of the preparation method of the present invention, the condensing agent is 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (ie EDCI), and the catalyst is 4-dimethylaminopyridine (ie DMAP). When EDCI is used as the condensation agent and DMAP is used as the catalyst, the target product not only has a high yield, but is also easier to purify.

As a preferred embodiment of the preparation method of the present invention, the reaction temperature of the Steglich esterification reaction is 0-45°C, the reaction time is 4-24h, the chrysin, the compound represented by the structural formula (2), the The molar ratio of the condensing agent and the catalyst is chrysin: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 present invention, the reaction temperature of the Steglich esterification reaction is normal temperature, the reaction time is 6h, the chrysin, the compound shown in the structural formula (2), the condensing agent and the The molar ratio of the catalyst is chrysin: compound shown in structural formula (2): condensing agent: catalyst = 1:1.5:1.5:0.5.

As a preferred embodiment of the preparation method of the present 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 includes the following steps: separating the solid from the liquid of the Steglich esterification system, collecting the solid and washing it with petroleum ether, ethyl acetate and acetone in sequence. After washing with petroleum ether, ethyl acetate and acetone in sequence, the impurities can be removed and the pure target product can be obtained. The purification method is very simple.

As a preferred embodiment of the preparation method of the present invention, the preparation method further includes the following step: performing drying treatment after the washing.

In the second aspect, the present invention provides chrysin cinnamate or derivatives thereof prepared by the above preparation method.

Compared with the prior art, the present invention has the following advantages: in the present invention, chrysin cinnamate or its derivatives are prepared by one-step process of chrysin and cinnamic acid or its derivatives. The yield is high, above 40%, and the obtained chrysin cinnamate or its derivatives have the characteristics of chrysin and cinnamic acid or its derivatives, providing a compound source for biological activity screening.

Description of drawings

Fig. 1 is the reaction route diagram of each embodiment (raw material 2a corresponds to product 3a, raw material 2b corresponds to product 3c...and so on, raw material 2n corresponds to product 3n);

Fig. 2 is the reaction mechanism of chrysin and cinnamic acid of the present invention.

Detailed ways

In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific examples.

The reagents adopted in each of the following embodiments are analytically pure, and the instruments used are respectively OptiMelt MPA100 type melting point analyzer (SRS company of the U.S.); standard); Thermo Fisher LCQ Fleet liquid chromatography-mass spectrometry (Thermo Fisher Seientific, USA).

Example 1

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2a)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and then dried to obtain compound 3a (chrysin cinnamate).

Obtained compound 3a: yellow solid, yield 95.1%, mp (melting point) 211.4～213.2°C; ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 12.87(s, 1H), 8.14(d, J=7.4Hz ,2H),7.95～7.82(m,2H),7.80(d,J＝8.8Hz,1H),7.63(dq,J＝14.7,7.1Hz,3H),7.51～7.45(m,1H),7.22( dd,J=11.2,2.1Hz,1H),7.18(d,J=2.6Hz,1H),7.02(s,1H),6.93(d,J=16.1Hz,1H),6.81～6.73(m,2H ); ¹³ CNMR (125MHz, DMSO-d ₆ ) δ: 182.15, 170.25, 164.80, 161.28, 159.04, 156.98, 138.96, 136.43, 133.26, 132.96, 131.27, 129.73, 129.30, 127.101, 101, 115.1 106.25, 105.96, 102.27; LC-MS (ESI) m/z: Calcd. for C ₂₄ H ₁₆ KO ₅ {[M+K] ⁺ } 423.06, found 423.18.

Example 2

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2b)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3b.

Compound 3b obtained: pale yellow solid, yield 82.4%, mp167.2～169.1℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 12.89(s, 1H), 8.15(d, J=7.1Hz, 2H ), 8.11(d, J＝15.9Hz, 1H), 7.87(d, J＝7.9Hz, 1H), 7.63(dt, J＝14.6, 7.0Hz, 3H), 7.42～7.35(m, 1H), 7.34 ~7.27(m,2H),7.24(d,J=2.0Hz,1H),7.19(s,1H),6.83(d,J=15.9Hz,1H),6.80(d,J=2.0Hz,1H) ,2.46(s,3H); ¹³ C NMR(125MHz,DMSO-d ₆ )δ:183.15,164.71,164.61,161.29,156.85,156.39,144.92,138.45,132.94,132.79,131.39,130.88,1129.41, , 127.07, 117.95, 108.81, 106.27, 105.94, 102.25, 19.79; LC-MS (ESI) m/z: Calcd. for C ₂₅ H ₁₉ O ₅ {[M+H] ⁺ } 399.12, Actual 399.04.

Example 3

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2c)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3c.

The obtained compound 3c: light yellow solid, yield 47.8%, mp182.1～183.6℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 12.88(s, 1H), 8.15(d, J=7.3Hz, 2H ),7.88(d,J=16.0Hz,1H),7.63(td,J=14.6,7.1Hz,5H),7.37(t,J=7.6Hz,1H),7.31(d,J=7.6Hz,1H ),7.23(d,J=2.0Hz,1H),7.19(s,1H),6.90(d,J=16.0Hz,1H),6.78(d,J=2.1Hz,1H),2.36(s,3H ); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 183.14, 164.71, 164.64, 161.28, 156.84, 156.42, 147.99, 138.82, 134.13, 132.94, 132.34, 130.87, 129.75, 129.712, 127. 116.85 , 108.79, 106.26, 105.93, 102.25, 21.32; LC-MS (ESI) m/z: C ₂₅ H ₁₈ NaO ₅ {[M+Na] ⁺ } 421.10, found 421.11.

Example 4

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2d)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3d.

The obtained compound 3d: yellow solid, yield 57.1%, mp190.2～192.5℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 12.88(s, 1H), 8.14(d, J=7.1Hz, 2H) ,7.89(d,J=16.0Hz,1H),7.73(d,J=8.1Hz,2H),7.62(dt,J=14.6,7.0Hz,3H),7.29(d,J=7.8Hz,2H) ,7.22(d,J=2.1Hz,1H),7.19(s,1H),6.86(d,J=16.0Hz,1H),6.78(d,J=2.0Hz,1H),2.36(s,3H) ; ¹³ C NMR(125MHz,DMSO-d ₆ )δ:183.14,164.74,164.70,161.28,156.84,156.47,147.88,141.80,132.93,131.52,130.88,130.16,129.70,129.35,110.191,1217. 06.26, 105.96, 102.26, 21.60; LC-MS (ESI) m/z: Calcd. for C ₂₅ H ₁₈ NaO ₅ {[M+Na] ⁺ } 421.10, found 421.09.

Example 5

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2e)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3e.

The obtained compound 3e: pale yellow solid, yield 77.7%, mp197.2～199.8℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 2.89(s,1H), 8.18–8.12(m,3H), 8.11(dd, J=7.9,1.5Hz,1H),7.69–7.58(m,4H),7.52(td,J=7.7,1.7Hz,1H),7.50–7.43(m,1H),7.25(d, J=2.0Hz, 1H), 7.19(s, 1H), 7.04(d, J=16.0Hz, 1H), 6.81(d, J=2.0Hz, 1H); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 183.16, 164.74, 164.30, 161.32, 156.86, 156.24, 142.15, 134.58, 133.07, 132.95, 131.73, 130.88, 130.63, 129.72, 129.16, 128.43, 127.195, 120.6, 120.6 05.94,102.27; LC-MS ( ESI) m/z: Calcd. for C ₂₄ H ₁₅ ClNaO ₅ {[M+Na] ⁺ } 441.05, found 441.04.

Example 6

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2f)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3f.

Obtained compound 3f: yellow solid, yield 55.2%, mp202.3～204.5℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 12.89(s, 1H), 8.14(d, J=7.1Hz, 2H) ,7.98(s,1H),7.91(d,J＝16.1Hz,1H),7.82(d,J＝7.6Hz,1H),7.69～7.57(m,3H),7.57～7.53(m,1H), 7.50(t, J=7.8Hz, 1H), 7.23(d, J=2.1Hz, 1H), 7.18(s, 1H), 7.03(d, J=16.0Hz, 1H), 6.79(d, J=2.1 Hz,1H); ¹³ CNMR(125MHz,DMSO-d ₆ )δ:183.14,164.74,164.42,161.30,156.85,156.32,146.15,136.44,134.33,132.95,131.32,131.15,130.87,1228.78, .16 , 118.86, 108.85, 106.27, 105.92, 102.25; LC-MS (ESI) m/z: Calcd. for C ₂₄ H ₁₅ ClKO ₅ {[M+K] ⁺ } 457.02, Actual 457.14.

Example 7

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2g)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3g.

The obtained compound 3g: light yellow solid, yield 88.7%, mp234.6～237.2℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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: C ₂₄ H ₁₆ ClO ₅ {[M+ H] ⁺ } calculated value 419.06, actual value 419.07.

Example 8

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2h)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3h.

The obtained compound 3h: yellow solid, yield 85.5%, mp225.2～227.6℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 12.89(s, 1H), 8.15(d, J=7.1Hz, 2H) ,7.91(d,J=16.0Hz,1H),7.82(d,J=8.5Hz,2H),7.68(d,J=8.5Hz,2H),7.62(dt,J=14.6,7.0Hz,3H) ,7.23(d,J=2.1Hz,1H),7.19(s,1H),6.98(d,J=16.1Hz,1H),6.79(d,J=2.0Hz,1H); ¹³ C NMR(125MHz, DMSO-d ₆ )δ: 183.15, 164.73, 164.51, 161.30, 156.85, 156.36, 146.49, 133.53, 132.95, 132.53, 131.22, 130.88, 129.71, 127.16, 125.09, 118.082, 106. 102.25; LC-MS (ESI) m/z: Calcd. for C ₂₄ H ₁₅ BrKO ₅ {[M+K] ⁺ } 500.97, found 501.05.

Example 9

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2i)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3i.

The obtained compound 3i: pale yellow solid, yield 43.4%, mp184.7～186.3℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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); ¹³ CNMR (125MHz, DMSO-d ₆ ) δ: 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, 117.187, 12 6,115.28 , 108.86, 106.29, 105.94, 102.26; LC-MS (ESI) m/z: Calcd. for C ₂₄ H ₁₅ FNaO ₅ {[M+Na] ⁺ } 425.07, Actual 425.08.

Example 10

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2j)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3j.

Compound 3j obtained: yellow solid, yield 72.5%, mp247.7～251.1℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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＝7.8 Hz, 1H), 7.15(s, 1H), 6.82(d, J=2.0Hz, 1H); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 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: C ₂₄ H ₁₅ NKO ₇ {[M+K] ⁺ } The calculated value is 468.05, and the actual value is 468.20.

Example 11

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2k)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3k.

The obtained compound 3k: pale yellow solid, yield 89.9%, mp169.2～172.5℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 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: C ₂₅ H ₁₈ KO K] ⁺ } calculated value 453.07, actual value 453.19.

Example 12

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2l)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3l.

Obtained compound 3l: yellow solid, yield 73.4%, mp218.5～221.1℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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); ¹³ C NMR(125MHz, DMSO-d ₆ )δ: 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, 102.90, LC C ₂₅ H ₁₉ O ₆ {[M+H] ⁺ }calculated 415.17, actual 415.10.

Example 13

Add chrysin (compound represented by structural formula (1)) (1mmol, 1eq), cinnamic acid (compound represented by structural formula (2m)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3m.

The obtained compound 3m: yellow solid, yield 74.4%, mp172.3～174.5℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 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: C ₂₆ H ₂₀ NaO ₇ {[M+Na] ⁺ } The calculated value is 467.11, and the actual value is 467.10.

Example 14

In a 50mL round bottom flask, add chrysin (compound shown in structural formula (1)) (1mmol, 1eq), cinnamic acid (compound shown in structural formula (2n)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of N ₂ , add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is complete, suction filter, filter The cake was washed successively with petroleum ether, ethyl acetate and acetone, and dried to obtain compound 3n.

The obtained compound 3n: yellow solid, yield 90.6%, mp220.2～221.4℃; ¹ H NMR (500MHz, DMSO-d ₆ )δ: 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); ¹³ CNMR(125MHz,DMSO-d ₆ )δ:183.14,164.86,164.69,161.26,156.84,156.52,150.45,148.65,147.82,132.94,130.87,129.71,111.415,12 1 , 109.07, 108.74, 107.39, 106.24, 105.97, 102.27; LC-MS (ESI) m/z: Calcd. for C ₂₅ H ₁₇ O ₇ {[M+H] ⁺ } 429.10, found 429.10.

Comparative example 1

Chrysin (compound shown in structural formula (1)) (1mmol, 1eq) and cinnamic acid (compound shown in structural formula (2a)) (1.5mmol, 1.5eq.) were added successively in a 50mL round bottom flask, and then in N ₂ Under the protection of , dichloromethane (10.0 mL) was added and reacted at room temperature for about 6 h (TLC detection). It was found that the reaction could not proceed, and the target product compound 3a could not be obtained.

Comparative example 2

Chrysin (compound represented by structural formula (1)) (1mmol, 1eq), cinnamic acid (compound represented by structural formula (2a)) (1.5mmol, 1.5eq.), DCC (N, N'-dicyclohexylcarboimide, 1.5mmol, 1.5eq) and DMAP (0.5mmol, 0.5eq), then under the protection of _N2 , dichloromethane (10.0mL) was added, and the reaction was carried out at room temperature for about 8h ( TLC detection), after the reaction was completed, suction filtration, the filter cake was washed with petroleum ether, ethyl acetate, acetone successively, and dried to obtain compound 3a with a yield of 84.6%, but the obtained compound 3a still contained impurities.

Comparative example 3

Add dichloromethane (10.0mL), cinnamic acid (compound represented by structural formula (2a)) (1.5mmol, 1.5eq.) and thionyl chloride (1.5mmol, 1.5eq.) in sequence in a 50mL round bottom flask, React at room temperature for about 8 hours, concentrate to remove the solvent, and then dissolve in dichloromethane (10.0mL), add chrysin (compound represented by structural formula (1)) (1mmol, 1eq) to the system, and react at room temperature for about 8h (TLC detection), after the reaction was completed, suction filtration was performed, and the filter cake was washed with petroleum ether, ethyl acetate, and acetone in sequence, and then dried to obtain compound 3a with a yield of 86.5%.

Comparing Example 1 and Comparative Example 1-3, it can be seen that when no other catalyst reagents are added, the reaction cannot be carried out; under the action of EDCI and DMAP, the reaction can be completed within 6h, and the yield reaches 95.1%, and the resulting product is purified by petroleum Ether, ethyl acetate, and acetone are washed in sequence to achieve purity; under the action of DCC and DMAP, the reaction time is longer, the yield is significantly reduced, and the resulting product is more difficult to purify; use _SOCl2 to acylate cinnamic acid Esterification with chrysin requires less reaction time, but two-step reaction is required, the yield is slightly lower, and the reaction conditions are relatively harsh, so it is most appropriate to choose the conditions of EDCI and DMAP to carry out the reaction.

On the basis of experimental results and literature reports ^[16-18] , the inventor speculated on the possible reaction mechanism (see Figure 2). First, cinnamic acid reacted with EDCI to generate more active O-acylisourea, and then chrysin C The hydroxyl group at the -7 position attacks the O-acylisourea to generate the corresponding ester and EDCI by-products. At the same time, in order to prevent the 1,3-rearrangement of O-acylisourea in this 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 to illustrate the technical solutions of the present invention rather than limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that The technical solution of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solution of the present invention.

references

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Claims (2)

1. a preparation method of chrysin cinnamate, it is characterized in that, described preparation method comprises the following steps: the compound shown in chrysin and structural formula (2) generates Steglich in organic solvent under condensation agent and catalyst effect Esterification reaction to obtain the chrysin cinnamate, the structural formula of the chrysin cinnamate is shown in formula (3);

; The n is 0; the condensing agent is 1-ethyl-3-(3-dimethylpropylamine) carbodiimide, and the catalyst is 4-dimethylaminopyridine; The reaction temperature of the Steglich esterification reaction is normal temperature, the reaction time is 6h, the molar ratio of the chrysin, the compound shown in the structural formula (2), the condensation agent and the catalyst is chrysin: structural formula ( 2) Compound shown: condensing agent: catalyst = 1:1.5:1.5:0.5; Described organic solvent is methylene dichloride; The preparation method also includes the following steps: separating the solid from the liquid after the Steglich esterification reaction, collecting the solid and washing it with petroleum ether, ethyl acetate and acetone in sequence, and then drying. 2. preparation method according to claim 1, is characterized in that, described Steglich esterification is carried out under the protection of protective gas.

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