CN114933547A - Pterostilbene N-phenylamide compound and preparation method and application thereof - Google Patents

Pterostilbene N-phenylamide compound and preparation method and application thereof Download PDF

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CN114933547A
CN114933547A CN202210545669.3A CN202210545669A CN114933547A CN 114933547 A CN114933547 A CN 114933547A CN 202210545669 A CN202210545669 A CN 202210545669A CN 114933547 A CN114933547 A CN 114933547A
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cdcl
nmr
pterostilbene
chloride
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阮班锋
李谨
王可
张浩苏
刘静静
张敏
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Tobacco Industry Development Center Xuanzhou District Xuancheng City
Hefei University
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Hefei University
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Abstract

The invention discloses a pterostilbene N-phenyl amide compound and a preparation method and application thereof, and relates to the technical field of pharmaceutical chemistry, wherein a series of pterostilbene amide compounds with novel structures are designed and synthesized, and the structures of the compounds are characterized; the method for preparing the compounds has the characteristics of easily obtained raw materials, simple and convenient operation and high yield, and can quickly synthesize the target compounds; the anti-inflammatory activity of the compounds is tested at the same time, and the compounds with high activity are screened out to be used for developing novel anti-inflammatory drugs.

Description

Pterostilbene N-phenylamide compound and preparation method and application thereof
The technical field is as follows:
the invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a pterostilbene N-phenylamide compound and a preparation method and application thereof.
Background art:
the Pterostilbene (Pterostilbene) structure contains stilbene and two methoxy structures, also known as 4' -hydroxy-3, 5-dimethoxy stilbene. The pterostilbene is a natural product and has various biological activities, wherein the more prominent activities comprise anti-inflammation, antibiosis, antioxidation and the like, and the pterostilbene mainly exists in pterocarpus indicus, grapes and blueberries. Compared with another natural product resveratrol with a similar structure, pterostilbene has stronger lipophilicity, which is derived from two methoxyl structures contained in a pterostilbene skeleton, and the characteristic plays a non-negligible role in enhancing the stability of the pterostilbene and improving the cell uptake and the intestinal permeability. In addition, the pterostilbene is a natural product, has low toxicity and is not easy to cause adverse reaction, so the pterostilbene can be used as a mother nucleus structure to be applied to the design and development of new drugs and used for treating and preventing related diseases, and the wide depth of field before application is concerned by researchers. However, pterostilbene has the defects of weak activity strength, low bioavailability, undefined target spot and the like, and the medicinal value of the pterostilbene is severely limited, so that the development of a novel pterostilbene derivative is very necessary to solve and overcome the defects.
The invention content is as follows:
the technical problem to be solved by the invention is to design and synthesize pterostilbene N-phenylamide compounds with novel structures, test the anti-inflammatory activity of the compounds, and screen out high-activity compounds from the compounds for developing novel anti-inflammatory drugs.
The invention aims to provide a pterostilbene N-phenylamide compound, which has a structure shown in a formula I:
Figure BDA0003652550870000011
Figure BDA0003652550870000021
wherein R is 1 Is methyl or propargyl; r 2 Is phenyl; r 3 Is phenyl, substituted phenyl, thienyl, furyl or C1-5 alkyl, substituted alkyl, cycloalkyl, alkenyl, ether group or ester group.
The pterostilbene N-phenylamide compounds specifically include compounds D1-41 in the following Table 1.
TABLE 1
Figure BDA0003652550870000022
Figure BDA0003652550870000031
The second purpose of the invention is to provide a preparation method of the pterostilbene N-phenylamide compound, which is prepared by pterostilbene and R 1 Reacting the intermediate A1-2 with the intermediate X, reacting the intermediate A1-2 with phosphorus oxychloride to obtain an intermediate B1-2, and reacting the intermediate B1-2 with the intermediate R 2 -NH 2 Reacting to obtain a compound C1-2, and reacting the intermediate C1-2 with R 3 COCl reaction to obtain the compound D1-41.
The synthetic route is as follows:
Figure BDA0003652550870000041
wherein R is 1 Is methyl or propargyl; r is 2 Is phenyl; r 3 Is phenyl, substituted phenyl, thienyl, furyl or alkyl, substituted alkyl, cycloalkyl, alkenyl, ether group or ester group with 1-5 carbon atoms;
when R is 1 When is methyl, X is I; when R is 1 In the case of propargyl, X is Br.
The third purpose of the invention is to provide the application of the pterostilbene N-phenylamide compound in preparing anti-inflammatory drugs.
The invention has the beneficial effects that: the invention designs and synthesizes a series of pterostilbene amide compounds with novel structures, and the structures of the compounds are characterized; the method for preparing the compounds has the characteristics of easily obtained raw materials, simple and convenient operation and high yield, and can quickly synthesize the target compounds; the anti-inflammatory activity of the compounds is tested at the same time, and the compounds with high activity are screened out to be used for developing novel anti-inflammatory drugs.
Description of the drawings:
FIG. 1 shows the safety evaluation of compound D1-41 of the present invention against RAW264.7 cells;
FIG. 2 shows the inhibitory effect (inhibition rate) of the compound D1-41 of the present invention on LPS-induced NO release from RAW264.7 cells;
FIG. 3 shows the inhibitory effect (inhibition rate) of the compound D1-41 of the present invention on IL-1. beta. release from BMDMs cells induced by LPS/Nigericin.
The specific implementation mode is as follows:
in order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described in the following combined with the specific embodiments.
Example 1
1) Synthesis of intermediate a 1:
0.01mol of pterostilbene and 0.01mol of anhydrous potassium carbonate are weighed, dissolved in 10mL of acetone, stirred uniformly, and then 0.04mol of methyl iodide is added into a reaction system in a dropwise manner. After the dropwise addition, heating the reaction system to reflux, reacting for 24 hours, cooling the reaction system to room temperature, filtering, collecting filtrate, drying and distilling to obtain a crude product, and purifying the crude product by column chromatography to obtain an intermediate A1.
2) Synthesis of intermediate B1:
weighing 0.01mol of intermediate A1, dissolving in a mixed solvent of 50mL acetonitrile and 0.01mol of DMF, dropwise adding 0.015mol of phosphorus oxychloride under the ice bath condition, transferring to room temperature after half an hour of dropwise adding, stirring for reaction for two hours, then adding 300mL of cold water into the reaction system, stirring for two hours, ending the experiment, and extracting for 3 times by using 100mL of ethyl acetate. The organic layer was backwashed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected, followed by dry distillation to give a crude product, which was purified by column chromatography to give intermediate B1.
3) Synthesis of intermediate C1:
0.01mol of intermediate B1 and 0.012mol of aniline are weighed and dissolved in 10mL of methanol, stirred evenly and transferred into an ice bath, and 0.02mol of NaBH is added 3 CN is added into the mixed solution one by one, 200 mu L of acetic acid is added into the mixed solution for ice bath stirring for 1h, the mixed solution is turned to normal temperature for overnight reaction, the reaction solution is gradually clarified, the experiment is ended, 10mL of water is added under ice bath, excessive methanol is evaporated, 100mL of ethyl acetate is used for extraction for 3 times, the organic layer is backwashed by water, anhydrous sodium sulfate is used for drying and filtering, the filtrate is collected, then the crude product is obtained by drying and distillation, and the crude product is purified by column chromatography to obtain an intermediate C1.
4) Synthesis of (E) -N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -N-phenylbenza-mide (Compound D1):
0.01mol of intermediate C1 and 0.005mol of DMAP are weighed and dissolved in 4mL of dichloromethane, 0.03mol of benzoyl chloride is dropwise added under ice bath, then 0.02mol of triethylamine is dropwise added, the mixture is stirred for three minutes in ice bath and then is reacted for 1 hour at room temperature, and the experiment is finished and is extracted for 3 times by 50mL of ethyl acetate. The organic layer was backwashed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected, and then dried and distilled to obtain a crude product, which was purified by column chromatography and then recrystallized from anhydrous ethanol to obtain compound D1.
1 H NMR(400MHz,CDCl 3 )δ7.61(t,J＝15.5Hz,3H),7.03(ddd,J＝31.4,19.1,6.0Hz,11H),6.86–6.67(m,3H),6.17(d,J＝2.2Hz,1H),5.46(s,2H),3.84(d,J＝13.2Hz,6H),3.52(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ169.32,160.09,159.71,159.58,141.48,139.38,137.30,130.68,130.48,130.34,129.25,129.06,128.58,128.43,128.11,128.02,127.08,123.94,115.08,114.65,101.65,97.86,56.51,56.03,55.64,55.54,40.59,40.38,40.18,39.97,39.76,39.55,39.34.
Example 2
(E) Synthesis of N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -4-methyl-N-phenylbenzamide (Compound D2):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with p-methylbenzoyl chloride to give compound D2.
1 H NMR(400MHz,CDCl 3 )δ7.62(t,J＝13.1Hz,3H),7.05(d,J＝7.9Hz,2H),7.00–6.93(m,6H),6.85(d,J＝7.9Hz,2H),6.79(dd,J＝7.6,1.9Hz,2H),6.75(d,J＝2.3Hz,1H),6.17(d,J＝2.3Hz,1H),5.47(s,2H),3.83(d,J＝13.9Hz,6H),3.52(s,3H),2.18(s,3H). 13 C NMR(101MHz,CDCl 3 )δ169.99,159.87,159.47,159.38,141.77,139.85,138.85,133.81,130.40,130.24,128.77,128.36,128.28,128.15,127.91,126.42,124.72,124.56,115.59,114.18,101.14,97.20,55.42,55.35,55.25,21.25.
Example 3
(E) Synthesis of N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -2-methyl-N-phen-ylbenzamide (Compound D3):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with o-methylbenzoyl chloride to give compound D3.
1 H NMR(400MHz,CDCl 3 )δ7.74–7.61(m,3H),7.06(d,J＝16.0Hz,1H),6.93(ddd,J＝19.7,9.9,3.9Hz,8H),6.82(dd,J＝14.0,7.8Hz,4H),6.15(d,J＝2.1Hz,1H),5.47(s,2H),3.83(d,J＝6.1Hz,6H),3.41(s,3H),2.21(s,3H). 13 C NMR(101MHz,CDCl 3 )δ167.97,160.15,159.54,159.42,141.24,140.54,139.86,131.45,130.72,130.03,128.75,128.59,128.30,128.25,127.27,124.45,118.25,114.73,114.26,112.30,101.47,97.25,55.44,55.34,55.25,41.40.
Example 4
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -2-fluoro-N-phen-ylbenzamide (Compound D4):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with o-fluorobenzoyl chloride to give compound D4.
1 HNMR(400MHz,CDCl 3 )δ7.64(t,J＝12.7Hz,3H),7.03(dd,J＝14.9,7.3Hz,3H),6.95(dd,J＝9.1,5.4Hz,5H),6.87–6.76(m,4H),6.71(t,J＝8.8Hz,1H),6.15(d,J＝2.1Hz,1H),5.45(s,2H),3.80(d,J＝3.6Hz,6H),3.43(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.02,160.02,159.52,159.41,140.15,139.83,130.67,130.33,130.25,130.16,128.83,128.32,127.73,127.09,124.16,123.64,115.36,115.15,115.00,114.22,101.08,97.19,55.35,55.32,55.26,41.08.
Example 5
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -3-fluoro-N-phen-ylbenzamide (Compound D5):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with m-fluorobenzoyl chloride to give compound D5.
1 H NMR(400MHz,CDCl 3 )δ7.57(dd,J＝29.7,12.3Hz,3H),6.98(dt,J＝20.0,7.6Hz,7H),6.88–6.70(m,6H),6.17(d,J＝2.2Hz,1H),5.44(s,2H),3.85(d,J＝13.0Hz,6H),3.52(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.50,163.04,160.59,160.01,159.49,159.44,141.07,139.90,138.89,138.82,130.64,130.10,129.20,129.12,128.72,128.23,128.10,126.90,124.46,123.88,123.85,115.93,115.72,115.45,115.22,115.13,114.26,101.26,97.22,55.42,55.35,55.26.
Example 6
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxy-phenyl) benzyl) -4-fluoro-N-phen-ylbenzamide (Compound D6):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with p-fluorobenzoyl chloride to give compound D6.
1 H NMR(400MHz,CDCl 3 )δ7.59(dd,J＝21.4,12.4Hz,3H),7.10(dd,J＝8.5,5.5Hz,2H),7.03–6.93(m,6H),6.74(ddd,J＝19.4,10.7,5.8Hz,5H),6.17(d,J＝2.3Hz,1H),5.45(s,2H),3.83(d,J＝13.6Hz,6H),3.51(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.94,163.87,161.39,160.01,159.46,141.47,139.85,132.86,132.83,130.51,130.49,130.41,130.18,128.74,128.26,128.09,126.74,124.55,115.29,114.68,114.46,114.22,101.31,97.23,55.42,55.32,55.23,41.53.
Example 7
(E) Synthesis of 2-chloro-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbenzamide (Compound D7):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with o-chlorobenzoyl chloride to give compound D7.
1 H NMR(400MHz,CDCl 3 )δ7.71–7.62(m,9H),7.08(dd,J＝10.1,2.7Hz,5H),7.04–6.93(m,24H),6.91(dd,J＝7.2,3.8Hz,7H),6.81(d,J＝2.3Hz,3H),6.13(d,J＝2.3Hz,3H),5.43(s,6H),3.83(d,J＝1.5Hz,18H),3.40(s,9H). 13 C NMR(101MHz,CDCl 3 )δ167.45,160.05,159.56,159.41,140.02,139.82,136.89,130.69,130.27,130.11,129.27,129.17,128.81,128.53,128.41,127.79,127.27,125.98,124.37,124.19,114.96,114.20,100.97,97.14,55.31,55.27,40.92.
Example 8
(E) -Synthesis of 3-chloro-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbenzamide (Compound D8):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with m-chlorobenzoyl chloride to give compound D8.
1 H NMR(400MHz,CDCl 3 )δ7.57(dd,J＝32.3,12.2Hz,3H),7.14–7.05(m,2H),7.04–6.95(m,6H),6.94–6.87(m,2H),6.80–6.71(m,3H),6.17(d,J＝2.2Hz,1H),5.44(s,2H),3.85(d,J＝14.5Hz,6H),3.52(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.36,160.01,159.52,159.42,141.00,139.94,138.45,133.60,130.69,130.06,128.95,128.71,128.47,128.23,128.13,126.93,126.17,124.52,115.08,114.28,101.31,97.23,55.44,55.36,55.26.
Example 9
(E) Synthesis of 4-chloro-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbenzamide (Compound D9):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with p-chlorobenzoyl chloride to give compound D9.
1 H NMR(400MHz,CDCl 3 )δ7.58(dd,J＝25.4,12.3Hz,3H),7.08–6.90(m,10H),6.81–6.68(m,3H),6.16(d,J＝2.3Hz,1H),5.44(s,2H),3.83(d,J＝14.8Hz,6H),3.51(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.81,167.54,160.01,159.46,159.44,141.25,139.87,135.19,134.79,130.56,130.14,129.68,128.71,128.25,128.14,127.78,126.84,124.54,115.20,114.23,101.32,97.23,55.43,55.34,55.25,41.52.
Example 10
(E) -Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phenylcyclo-he-xanecarboxamide (Compound D10):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced by cyclohexanecarbonyl chloride to give compound D10.
1 H NMR(400MHz,CD 3 OD)δ7.65(d,J＝8.7Hz,2H),7.55(d,J＝16.1Hz,1H),7.31–7.21(m,3H),7.17(d,J＝16.1Hz,1H),6.95(ddt,J＝6.9,4.9,2.9Hz,5H),6.21(d,J＝2.3Hz,1H),5.17(s,2H),3.84(s,3H),3.81(s,3H),3.34(s,3H),2.09–2.03(m,1H),1.61–1.26(m,10H). 13 C NMR(101MHz,CDCl 3 )δ175.85,175.14,159.90,159.79,159.56,159.31,159.15,157.67,141.29,141.17,139.55,133.06,130.21,130.08,129.57,128.84,128.46,128.36,127.38,127.29,124.19,116.08,114.07,113.08,100.74,97.18,55.47,55.33,55.25,55.14,55.04,54.86,54.76,41.83,41.63,40.51,29.33,25.74,25.63,25.49.
Example 11
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phenylmethacr-ylamide (Compound D11):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with methacryloyl chloride to give compound D11.
1 H NMR(400MHz,CDCl 3 )δ7.58(t,J＝5.7Hz,2H),7.47(d,J＝16.0Hz,1H),7.14–7.08(m,3H),6.95(ddd,J＝8.1,7.0,5.7Hz,3H),6.88–6.81(m,2H),6.75(d,J＝2.3Hz,1H),6.14(d,J＝2.3Hz,1H),5.29(s,2H),4.81(d,J＝26.3Hz,2H),3.82(d,J＝6.7Hz,6H),3.44(s,3H),1.63(s,3H). 13 C NMR(101MHz,CDCl 3 )δ171.19,159.89,159.46,159.36,141.30,141.21,139.76,130.39,130.11,128.58,128.29,128.02,126.98,124.29,117.87,115.48,114.15,101.08,97.22,55.40,55.31,55.26,20.56.
Example 12
(E) Synthesis of N- (2,4-dimethoxy-6- ((E) -4-methoxystyryl) benzyl) -N-phenylbut-2-enamide (Compound D12):
the preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with 2-butenoyl chloride to obtain compound D12.
1 H NMR(400MHz,CDCl 3 )δ7.54(dd,J＝34.7,12.3Hz,3H),7.24–7.15(m,3H),6.99–6.84(m,6H),6.75(d,J＝2.1Hz,1H),6.14(d,J＝2.1Hz,1H),5.59(d,J＝14.9Hz,1H),5.27(s,2H),3.85(d,J＝10.0Hz,6H),3.41(s,3H),1.67(d,J＝6.7Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ165.17,159.83,159.50,159.30,140.85,140.79,139.73,130.33,130.19,129.11,128.41,128.30,127.33,124.45,123.36,115.74,114.08,100.91,97.17,55.36,55.33,55.25,40.86,18.00.
Example 13
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxy) benzyl) -N-phenylisobuty-ramide (Compound D13):
the procedure was as in example 1 except that benzoyl chloride in example 1 was replaced with isobutyryl chloride to give compound D13.
1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.7Hz,2H),7.43(d,J＝16.0Hz,1H),7.23–7.15(m,3H),6.96(dd,J＝15.7,12.4Hz,3H),6.89–6.76(m,3H),6.11(d,J＝2.2Hz,1H),5.20(s,2H),3.85(d,J＝5.4Hz,6H),3.34(s,3H),2.32(dt,J＝13.4,6.7Hz,1H),0.95(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ176.14,159.83,159.56,159.32,141.18,139.59,130.16,130.13,128.87,128.51,128.37,127.41,124.13,116.03,114.07,100.80,97.20,55.34,55.31,55.26,40.57,31.28,19.63.
Example 14
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxy) benzyl) -N-phenylcyclopropene-opanecarboxamide (Compound D14):
preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with cyclopropylcarbonyl chloride, to give compound D14.
1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝8.7Hz,2H),7.46(d,J＝16.0Hz,1H),7.23–7.16(m,3H),7.02–6.93(m,5H),6.79(d,J＝2.3Hz,1H),6.13(d,J＝2.3Hz,1H),5.25(s,2H),3.84(d,J＝8.3Hz,6H),3.39(s,3H),1.25–1.17(m,1H),1.03–0.97(m,2H),0.54–0.46(m,2H). 13 C NMR(101MHz,CDCl 3 )δ172.46,159.84,159.51,159.35,141.23,139.61,130.30,130.03,129.10,128.49,128.32,127.28,124.41,115.95,114.10,100.94,97.21,55.39,55.30,55.23,40.80,12.64,8.21.
Example 15
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxy) benzyl) -4-methyl-N-phen-yl-pentanamide (Compound D15):
preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with 4-methylpentanoyl chloride to give compound D15.
1 H NMR(400MHz,Acetone)δ7.66(d,J＝8.7Hz,2H),7.59(d,J＝16.1Hz,1H),7.29–7.22(m,3H),7.19–7.12(m,1H),6.96(ddd,J＝9.7,5.0,2.2Hz,4H),6.92(t,J＝3.2Hz,1H),6.23(d,J＝2.3Hz,1H),5.19(s,2H),3.82(d,J＝10.2Hz,6H),3.35(s,3H),1.98–1.91(m,2H),1.44–1.33(m,3H),0.65(d,J＝6.3Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ172.43,159.83,159.53,159.34,159.25,141.32,139.68,130.25,130.22,128.89,128.51,128.29,127.44,124.34,115.95,114.13,100.92,97.21,55.33,55.26,40.69,34.60,32.43,27.53,22.
Example 16
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phenylhexana-mid (Compound D16):
the procedure was as in example 1 except that benzoyl chloride in example 1 was replaced with hexanoyl chloride to give compound D16.
1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.7Hz,2H),7.46(d,J＝16.1Hz,1H),7.22–7.16(m,3H),7.01–6.92(m,3H),6.85(dd,J＝6.6,3.0Hz,2H),6.78(d,J＝2.3Hz,1H),6.12(d,J＝2.3Hz,1H),5.20(s,2H),3.85(d,J＝5.2Hz,6H),3.34(s,3H),1.94(t,J＝7.5Hz,2H),1.57–1.47(m,2H),1.16–1.02(m,4H),0.73(t,J＝6.8Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ172.25,159.84,159.54,159.34,141.32,139.62,130.23,130.19,128.96,128.52,128.29,127.42,124.28,115.95,114.13,100.86,97.18,55.32,55.25,40.69,34.37,31.43,25.37,22.38,13.83.
Example 17
(E) Synthesis of 4-chloro-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbutanamide (Compound D17):
preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with 4-chlorobutyryl chloride to obtain compound D17.
1 H NMR(400MHz,Acetone)δ7.65(d,J＝8.7Hz,2H),7.58(d,J＝16.1Hz,1H),7.30–7.23(m,3H),7.16(d,J＝16.1Hz,1H),7.00–6.94(m,4H),6.91(d,J＝2.2Hz,1H),6.23(d,J＝2.2Hz,1H),5.20(s,2H),3.88–3.78(m,6H),3.51(t,J＝6.5Hz,2H),3.35(s,3H),2.12–2.06(m,2H),1.98(dd,J＝13.3,6.7Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ170.70,159.93,159.54,159.40,140.85,139.65,130.31,130.16,128.87,128.71,128.21,127.68,124.30,115.65,114.16,101.00,97.23,55.34,55.27,44.59,40.86,31.28,28.25.
Example 18
(E) -Synthesis of 3-chloro-N- (2,4-dimethoxy-6- (4-methoxy) benzyl) -N-phen-ylpropanamide (Compound D18):
the preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with 3-chloropropionyl chloride to give compound D18.
1 H NMR(400MHz,CDCl 3 )δ7.57(t,J＝5.9Hz,2H),7.42(d,J＝16.1Hz,1H),7.25–7.17(m,3H),6.99–6.91(m,3H),6.90–6.84(m,2H),6.76(d,J＝2.4Hz,1H),6.13(t,J＝2.7Hz,1H),5.21(s,2H),3.86(d,J＝2.1Hz,3H),3.84(d,J＝2.8Hz,3H),3.76–3.70(m,2H),3.36(s,3H),2.42(t,J＝6.9Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ168.55,160.00,159.53,159.41,140.40,139.75,130.48,130.12,128.97,128.80,128.49,128.26,127.88,124.14,115.26,114.15,101.01,97.17,55.34,55.31,55.27,41.01,40.19,37.37.
Example 19
(E) -Synthesis of 2-chloro-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylpropanamide (Compound D19):
the preparation was carried out as described in example 1, except that benzoyl chloride in example 1 was replaced by 2-chloropropionyl chloride, to give compound D19.
1 H NMR(400MHz,CDCl 3 )δ7.60–7.54(m,4H),7.36(d,J＝16.0Hz,2H),7.26(d,J＝17.6Hz,9H),7.01–6.91(m,6H),6.76(t,J＝7.6Hz,4H),6.12(d,J＝2.3Hz,2H),5.31(d,J＝14.1Hz,2H),5.12(d,J＝14.2Hz,2H),4.15(q,J＝6.6Hz,2H),3.85(d,J＝5.0Hz,12H),3.35(d,J＝6.3Hz,6H),1.49(d,J＝6.6Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ171.19,159.89,159.46,159.36,141.30,141.21,139.76,130.39,130.11,128.58,128.29,128.02,126.98,124.29,117.87,115.48,114.15,101.08,97.22,55.40,55.31,55.26,40.73,20.56.
Example 20
(E) -Synthesis of 2-chloro-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylacetamide (Compound D20):
the procedure is as in example 1, except that the benzoyl chloride in example 1 is replaced by chloroacetyl chloride to give compound D20.
1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝8.7Hz,2H),7.38(d,J＝16.1Hz,1H),7.26–7.20(m,3H),7.00–6.90(m,5H),6.76(d,J＝2.3Hz,1H),6.13(d,J＝2.3Hz,1H),5.21(s,2H),3.85(d,J＝6.7Hz,6H),3.75(s,2H),3.38(s,3H). 13 C NMR(101MHz,CDCl 3 )δ165.43,160.13,159.51,159.45,139.85,139.68,130.83,129.99,128.90,128.75,128.31,123.73,114.62,114.21,101.03,97.12,55.33,55.28,41.99,41.84.
Example 21
(E) Synthesis of 4-bromo-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbenzamide (Compound D21):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with 4-bromobenzoyl chloride to give compound D21.
1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.7Hz,3H),7.17(d,J＝8.4Hz,2H),7.02–6.90(m,8H),6.79–6.71(m,3H),6.16(d,J＝2.3Hz,1H),5.43(s,2H),3.84(d,J＝15.2Hz,6H),3.51(s,3H). 13 C NMR(101MHz,CDCl 3 )δ159.45,159.42,141.21,139.89,135.64,130.72,130.56,130.11,129.88,128.70,128.24,128.14,126.84,124.54,123.18,115.20,114.21,101.28,97.23,55.43,55.36,55.26.
Example 22
(E) -Synthesis of 2-bromo-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbenzamide (Compound D22):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with 2-bromobenzoyl chloride, to give compound D22.
1 H NMR(400MHz,CDCl 3 )δ7.75–7.65(m,3H),7.26–7.20(m,1H),7.06(d,J＝16.0Hz,1H),6.99–6.89(m,9H),6.88–6.80(m,2H),6.12(d,J＝2.3Hz,1H),5.44(s,2H),3.78(d,J＝6.4Hz,6H),3.36(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.09,160.14,159.59,159.45,140.02,139.75,138.89,132.33,130.68,130.13,129.44,128.91,128.75,128.51,128.09,127.84,127.36,126.52,124.29,119.36,114.86,114.21,101.07,97.10,55.26,55.24,55.22,40.95.
Example 23
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxy-phenyl) benzyl) -2-iodo-N-phenyl-benzamide (Compound D23):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with o-iodobenzoyl chloride to give compound D23.
1 H NMR(400MHz,CDCl 3 )δ7.73–7.63(m,3H),7.30–7.23(m,1H),7.05(d,J＝16.0Hz,1H),7.00–6.86(m,10H),6.81(d,J＝2.3Hz,1H),6.13(d,J＝2.3Hz,1H),5.43(s,2H),3.82(d,J＝3.5Hz,6H),3.38(s,3H). 13 C NMR(101MHz,CDCl 3 )δ169.49,160.07,159.57,159.42,142.84,140.55,140.11,139.85,138.83,130.69,130.14,129.26,129.16,128.53,128.46,127.78,127.26,127.07,124.53,114.99,114.20,100.97,97.10,93.31,55.32,55.27,55.23,41.16.
Example 24
(E) Synthesis of N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -4-iodo-N-phenyl-benzamide (Compound D24):
the preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with iodobenzoyl chloride to obtain compound D24.
1 H NMR(400MHz,CDCl 3 )δ7.57(dd,J＝27.0,12.3Hz,3H),7.37(d,J＝8.3Hz,2H),6.97(ddd,J＝16.7,9.2,6.9Hz,6H),6.82(d,J＝8.1Hz,2H),6.78–6.71(m,3H),6.16(d,J＝2.3Hz,1H),5.43(s,2H),3.84(d,J＝16.0Hz,6H),3.51(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.92,160.01,159.46,159.43,141.18,139.88,136.67,136.24,130.56,130.12,129.94,128.70,128.25,128.16,126.87,124.53,115.18,114.23,101.33,97.23,95.32,55.44,55.36,55.26,41.50.
Example 25
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -2-methoxy-N-phenyl benzamide (Compound D25):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with o-methoxybenzoyl chloride to give compound D25.
1 H NMR(400MHz,CDCl 3 )δ7.69(dd,J＝12.3,3.6Hz,3H),7.09–7.00(m,2H),6.99–6.88(m,6H),6.85–6.78(m,3H),6.64(t,J＝7.4Hz,1H),6.54(d,J＝8.3Hz,1H),6.12(d,J＝2.2Hz,1H),5.42(s,2H),3.84(d,J＝3.5Hz,6H),3.51(s,3H),3.41(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.50,159.86,159.53,159.34,154.79,140.61,139.73,130.31,130.27,129.57,128.75,128.42,128.10,127.26,127.07,126.73,124.36,119.93,115.51,114.20,110.21,100.89,97.17,55.36,55.31,55.24,54.81,40.60.
Example 26
(E) -Synthesis of 2-bromo-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylacetamide (Compound D26):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with 2-bromoacetyl chloride to give compound D26.
1 H NMR(400MHz,CDCl 3 )δ7.61–7.53(m,2H),7.38(d,J＝16.0Hz,1H),7.26–7.20(m,3H),7.01–6.90(m,5H),6.76(t,J＝2.6Hz,1H),6.13(t,J＝2.2Hz,1H),5.21(d,J＝4.3Hz,2H),3.85(d,J＝6.4Hz,6H),3.75(s,1H),3.58(s,1H),3.38(d,J＝4.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ160.12,159.51,140.00,139.85,130.83,130.03,128.90,128.79,128.71,128.37,128.31,128.28,123.69,114.70,114.21,114.18,100.97,97.11,55.33,55.28,41.98,41.78,27.32.
Example 27
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phenylprepion-amide (Compound D27):
the procedure is as in example 1 except that the benzoyl chloride in example 1 is replaced by propionyl chloride to give compound D27.
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.7Hz,2H),7.47(d,J＝16.1Hz,1H),7.23–7.16(m,3H),7.01–6.92(m,3H),6.89–6.83(m,2H),6.78(d,J＝2.3Hz,1H),6.12(d,J＝2.3Hz,1H),5.21(s,2H),3.85(d,J＝6.8Hz,6H),3.35(s,3H),1.96(q,J＝7.5Hz,2H),1.00(t,J＝7.5Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ172.90,159.83,159.53,159.33,141.27,139.65,130.24,130.18,128.88,128.57,128.28,127.44,124.36,115.94,114.14,100.93,97.22,55.36,55.32,55.26,40.75,27.86,9.83.
Example 28
(E) -Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phenylthiophe-ne-2-carboxamide (Compound D28):
preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with 2-thenoyl chloride to obtain compound D28.
1 H NMR(400MHz,CDCl 3 )δ7.63–7.51(m,3H),7.27–7.16(m,4H),6.99–6.91(m,5H),6.77(d,J＝2.4Hz,1H),6.72(dd,J＝5.0,3.9Hz,1H),6.57(dd,J＝3.8,1.1Hz,1H),6.16(d,J＝2.3Hz,1H),5.40(s,2H),3.84(t,J＝4.9Hz,6H),3.44(s,3H). 13 C NMR(101MHz,CDCl 3 )δ161.60,160.01,159.65,159.35,140.87,139.91,138.89,131.82,130.43,130.21,129.79,128.59,128.32,128.09,126.52,124.20,115.19,114.13,100.94,97.17,55.38,55.34,55.27,42.34.
Example 29
(E) Synthesis of N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -2-ethyl-N-phenyl-butanamide (Compound D29):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with 2-ethylbutyryl chloride to give compound D29.
1 H NMR(400MHz,CDCl 3 )δ7.60–7.55(m,2H),7.49(d,J＝16.1Hz,1H),7.23–7.16(m,3H),7.02–6.91(m,3H),6.87–6.77(m,3H),6.10(d,J＝2.3Hz,1H),5.24(s,2H),3.85(d,J＝5.8Hz,6H),3.32(s,3H),2.00(ddd,J＝10.6,6.9,4.3Hz,1H),1.66–1.54(m,2H),1.37–1.25(m,2H),0.71(t,J＝7.4Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ174.98,159.84,159.61,159.29,141.10,139.43,130.26,130.17,129.70,128.34,128.32,127.32,124.06,116.06,114.01,100.49,97.07,55.30,55.24,55.18,45.51,40.67,26.10,12.14.
Example 30
(E) -Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -2-methoxy-N-ph-enylacetamide (Compound D30):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with methoxyacetyl chloride to give compound D30.
1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.6Hz,2H),7.47(d,J＝16.0Hz,1H),7.25–7.18(m,3H),6.99–6.91(m,3H),6.87(dd,J＝6.4,3.0Hz,2H),6.76(d,J＝2.0Hz,1H),6.12(d,J＝2.0Hz,1H),5.20(s,2H),3.84(d,J＝4.4Hz,6H),3.67(s,2H),3.35(s,3H),3.27(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.17,160.01,159.58,159.40,139.72,139.47,130.59,130.07,128.81,128.79,128.25,128.02,124.00,115.08,114.21,100.98,97.10,70.65,59.08,55.33,55.27,55.24,41.10.
Example 31
(E) Synthesis of 2- ((2,4-dimethoxy-6- (4-methoxystyryl) benzyl) (phenyl) amino) -2-oxoethyl acetate (Compound D31):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with acetoxyacetyl chloride to give compound D31.
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝8.6Hz,2H),7.38(d,J＝16.0Hz,1H),7.26–7.18(m,3H),6.94(dd,J＝9.4,2.9Hz,5H),6.75(d,J＝2.0Hz,1H),6.13(t,J＝4.4Hz,1H),5.18(s,2H),4.27(s,2H),3.85(d,J＝8.0Hz,6H),3.39(s,3H),2.09(d,J＝13.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.46,165.74,160.07,159.58,159.38,139.86,139.02,130.72,130.15,128.95,128.85,128.35,128.31,123.90,114.69,114.10,101.04,97.11,61.86,55.32,55.27,41.39,20.59.
Example 32
(E) Synthesis of N- (2,4-dimethoxy-6- (4-methoxy-phenyl) benzyl) -N-phenylcyclopropene-ntanecarboxamide (Compound D32):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with cyclopentylcarbonyl chloride to give compound D32.
1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.7Hz,6H),7.45(d,J＝16.0Hz,3H),7.18(dd,J＝6.5,3.7Hz,9H),6.98–6.91(m,8H),6.85(dd,J＝6.5,2.9Hz,6H),6.80(dd,J＝5.3,2.1Hz,4H),6.11(d,J＝2.2Hz,3H),5.21(s,6H),3.85(d,J＝6.4Hz,18H),3.33(s,9H),2.38(dd,J＝16.0,7.9Hz,4H),1.65–1.24(m,7H). 13 C NMR(101MHz,CDCl 3 )δ175.60,159.79,159.55,159.30,141.91,141.43,141.30,139.56,130.23,130.07,129.55,129.16,128.39,128.35,127.31,124.27,116.17,114.08,113.09,100.76,97.22,55.36,55.34,55.26,41.94,40.74,30.93,26.44,26.34.
Example 33
(E) -Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -2-phenoxy-N-phenyl-acetamide (Compound D33):
the procedure is as in example 1, except that the benzoyl chloride in example 1 is replaced by phenoxyacetyl chloride to give compound D33.
1 H NMR(400MHz,CDCl 3 )δ7.46(dd,J＝33.0,12.3Hz,3H),7.27–7.22(m,3H),7.11(t,J＝7.9Hz,2H),7.00–6.91(m,3H),6.85(dd,J＝17.0,8.0Hz,3H),6.76(dd,J＝13.0,5.1Hz,3H),6.14(d,J＝2.1Hz,1H),5.24(s,2H),4.30(s,2H),3.85(d,J＝7.1Hz,6H),3.37(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.80,160.08,159.62,159.39,158.19,139.77,139.29,130.76,129.95,129.25,128.95,128.72,128.27,123.67,121.06,114.85,114.62,114.20,100.95,97.10,66.40,55.31,55.28,55.26,41.34.
Example 34
(E) Synthesis of N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -N-phenylfuran-2-carboxamide (Compound D34):
preparation was carried out as in example 1, except that benzoyl chloride in example 1 was replaced with furoyl chloride to give compound D34.
1 H NMR(400MHz,CDCl 3 )δ7.53(dd,J＝23.1,12.4Hz,3H),7.33(s,1H),7.26–7.16(m,3H),6.99–6.90(m,5H),6.77(d,J＝2.2Hz,1H),6.18–6.09(m,2H),5.43(d,J＝2.8Hz,1H),5.36(s,2H),3.85(s,6H),3.43(s,3H). 13 C NMR(101MHz,CDCl 3 )δ160.05,159.69,159.35,158.52,147.10,144.18,140.89,139.92,130.60,130.15,129.36,128.50,128.26,127.92,124.05,116.03,115.01,114.18,110.80,100.99,97.14,55.32,55.27,41.94.
Example 35
(E) -Synthesis of N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phenylcyclobium-tanecoxamide (Compound D35):
preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with cyclobutylformyl chloride to obtain compound D35.
1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝8.7Hz,2H),7.47(d,J＝16.1Hz,1H),7.21–7.13(m,3H),7.01–6.92(m,3H),6.83–6.75(m,3H),6.12(d,J＝2.2Hz,1H),5.20(s,2H),3.85(d,J＝9.0Hz,6H),3.36(s,3H),2.84(dd,J＝10.3,6.6Hz,1H),2.34–2.18(m,2H),1.74–1.56(m,4H). 13 C NMR(101MHz,CDCl 3 )δ159.80,159.51,159.32,140.81,139.62,130.24,130.12,129.03,128.36,128.34,127.36,124.43,116.10,114.11,100.92,97.25,55.41,55.33,55.25,40.75,38.16,25.45,17.89.
Example 36
(E) Synthesis of N- (2, 4-dimethyl-6- (4-methoxystyryl) benzyl) -3,3-dimethyl-N-phenylbutanamide (Compound D36):
preparation was carried out in the same manner as in example 1 except that benzoyl chloride in example 1 was replaced with 3, 3-dimethylbutyryl chloride to give compound D36.
1 HNMR(400MHz,CDCl 3 )δ7.58(d,J＝8.6Hz,2H),7.45(d,J＝16.0Hz,1H),7.18(dd,J＝6.2,3.9Hz,3H),6.94(dd,J＝16.4,12.5Hz,3H),6.85–6.75(m,3H),6.12(d,J＝2.1Hz,1H),5.19(s,2H),3.85(d,J＝5.7Hz,6H),3.34(s,3H),1.91(s,2H),0.92(s,9H). 13 C NMR(101MHz,CDCl 3 )δ170.91,159.83,159.59,159.33,141.68,139.56,130.24,130.15,129.34,128.45,128.32,127.30,124.24,116.08,114.06,100.71,97.12,55.33,55.25,55.23,45.86,40.58,31.32,29.91.
Example 37
(E) Synthesis of 4-cyano-N- (2,4-dimethoxy-6- (4-methoxystyryl) benzyl) -N-phen-ylbenzamide (Compound D37):
preparation was carried out as in example 1 except that benzoyl chloride in example 1 was replaced with p-cyanobenzoyl chloride to give compound D37.
1 HNMR(400MHz,CDCl 3 )δ7.73–7.62(m,3H),6.93(ddd,J＝19.7,9.9,3.9Hz,8H),6.82(dd,J＝14.0,7.8Hz,4H),6.15(d,J＝2.1Hz,1H),5.47(s,2H),3.83(d,J＝6.1Hz,6H),3.41(s,3H). 13 C NMR(101MHz,CDCl 3 )δ164.90,164.83,162.41,150.09,149.45,140.65,131.90,128.31,128.23,128.00,127.67,127.64,121.52,115.97,115.75,103.71,63.71,43.50,17.61.
Example 38
1) Synthesis of intermediate a 2:
weighing 0.01mol of pterostilbene and 0.01mol of anhydrous potassium carbonate, adding 0.015mol of 3-bromopropyne, dissolving in 10mL of acetone, stirring uniformly, heating a reaction system to reflux, reacting for 24 hours, cooling the reaction system to room temperature, filtering, collecting filtrate, drying and distilling to obtain a crude product, and purifying the crude product by column chromatography to obtain an intermediate A2.
2) Synthesis of intermediate B2:
weighing 0.01mol of intermediate A2, dissolving in a mixed solvent of 50mL acetonitrile and 0.01mol of DMF, dropwise adding 0.015mol of phosphorus oxychloride under the ice bath condition, transferring to room temperature after half an hour of dropwise adding, stirring for reaction for two hours, then adding 300mL of cold water into the reaction system, stirring for two hours, ending the experiment, and extracting for 3 times by using 100mL of ethyl acetate. The organic layer was backwashed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected, and then dried and distilled to give a crude product, which was purified by column chromatography to give intermediate B2.
3) Synthesis of intermediate C2:
weighing 0.01mol of intermediate B2 and 0.012mol of aniline, dissolving in 10mL of methanol, stirring uniformly, transferring into an ice bath, and adding 0.02mol of NaBH 3 CN is added into the mixed solution one by one, 200 mu L of acetic acid is added into the mixed solution for ice bath stirring for 1h, the mixed solution is turned to normal temperature for overnight reaction, the reaction solution is gradually clarified, the experiment is ended, 10mL of water is added under ice bath, excessive methanol is evaporated, 100mL of ethyl acetate is used for extraction for 3 times, the organic layer is backwashed by water, anhydrous sodium sulfate is used for drying and filtering, the filtrate is collected, then the crude product is obtained by drying and distillation, and the crude product is purified by column chromatography to obtain an intermediate C2.
4) Synthesis of (E) -2-bromo-N- (2,4-dimethoxy-6- (4- (prop-2-yn-1-yloxy) styryl) benzyl) -N-phenyl-benzamide (Compound D38):
0.01mol of intermediate C2 and 0.005mol of DMAP are weighed and dissolved in 4mL of dichloromethane, 0.03mol of 2-bromobenzoyl chloride is dropwise added in ice bath, 0.02mol of triethylamine is dropwise added in the ice bath and stirred for three minutes, then the mixture is reacted for 1 hour at room temperature, the experiment is finished, and the mixture is extracted for 3 times by 50mL of ethyl acetate. The organic layer was backwashed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected, followed by dry distillation to give a crude product, which was purified by column chromatography and then recrystallized from anhydrous ethanol to give compound D38.
1 H NMR(400MHz,CDCl 3 )δ7.57(dd,J＝30.8,12.2Hz,3H),7.35–7.26(m,2H),7.12(d,J＝7.8Hz,2H),6.97(dt,J＝12.1,3.0Hz,6H),6.78–6.67(m,3H),6.16(d,J＝2.3Hz,1H),5.44(s,2H),3.83(d,J＝15.0Hz,6H),3.53–3.44(m,3H). 13 C NMR(101MHz,CDCl 3 )δ172.08,159.87,159.55,157.24,141.28,139.46,131.12,130.01,128.97,128.56,128.25,127.46,124.78,115.96,115.11,100.96,97.25,55.84,55.31,55.23,40.70,36.30,18.99,13.85.
Example 39
(E) Synthesis of N- (2,4-dimethoxy-6- (4- (prop-2-yn-1-yloxy) styryl) benzyl) -N-ph-phenylbutyramide (Compound D39):
the procedure was as in example 38, except for substituting 2-bromobenzoyl chloride in example 38 with n-butyryl chloride to give compound D39.
1 HNMR(400MHz,CDCl 3 )δ7.59(d,J＝8.7Hz,2H),7.49(d,J＝16.1Hz,1H),7.23–7.15(m,3H),6.99(dd,J＝17.8,12.2Hz,3H),6.88–6.73(m,3H),6.12(d,J＝1.7Hz,1H),5.20(s,2H),3.83(d,J＝1.6Hz,3H),3.33(s,3H),1.93(t,J＝7.4Hz,2H),1.63–1.49(m,2H),0.74(t,J＝7.4Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ162.64,161.47,160.29,159.53,157.37,139.81,138.42,130.97,130.89,128.73,128.39,128.36,128.32,124.11,115.09,113.77,101.35,97.18,61.29,55.80,55.30,55.25,40.51,13.48.
Example 40
Synthesis of methyl (E) -2- ((2,4-dimethoxy-6- (4- (prop-2-yn-1-yloxy) styryl) benzyl) (phenyl) amino) -2-oxoacetate (Compound D40):
the preparation method is the same as example 38, except that 2-bromobenzoyl chloride in example 38 is replaced by methylpentanoyl chloride to obtain compound D40.
1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.7Hz,2H),7.42(d,J＝16.0Hz,1H),7.24–7.15(m,3H),7.05–6.92(m,5H),6.74(d,J＝2.2Hz,1H),6.17(d,J＝2.2Hz,1H),5.21(s,2H),3.91(q,J＝7.1Hz,2H),3.83(d,J＝5.9Hz,3H),3.45(s,3H),0.87(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ162.63,161.47,160.26,159.53,157.36,139.89,138.46,131.01,130.91,128.77,128.37,128.31,124.17,115.12,113.85,101.30,97.21,78.53,75.61,61.30,55.84,55.29,40.59,13.48.
EXAMPLE 41
(E) -Synthesis of N- (2,4-dimethoxy-6- (4- (prop-2-yn-1-yloxy) styryl) benzyl) -N-phenyl cyclopropa specimen boxamide (Compound D41):
the procedure is as in example 38 except that 2-bromobenzoyl chloride in example 38 is replaced by cyclopropylcarbonyl chloride to give compound D41.
1 H NMR(400MHz,CDCl 3 )δ7.52(dd,J＝43.1,12.3Hz,3H),7.25–7.14(m,3H),7.06–6.93(m,5H),6.77(d,J＝2.2Hz,1H),6.14(d,J＝2.2Hz,1H),5.24(s,2H),3.84(s,3H),3.40(s,3H),1.19(ddd,J＝12.4,8.0,4.5Hz,1H),0.98(dt,J＝7.8,3.7Hz,2H),0.50(td,J＝6.7,3.5Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ172.48,159.80,159.49,157.21,141.23,139.52,131.17,129.83,129.08,128.47,128.27,127.25,124.95,116.07,115.08,100.94,97.29,55.86,55.41,55.26,40.79,12.60,8.21,0.02.
Evaluation of anti-inflammatory Activity
1. MTT method for detecting cytotoxicity
MTT method is adopted to detect the toxicity of the compound on RAW264.7 cells and HepaRG cells.
(1) Cell plating: collecting cells in logarithmic growth phase according to cell growth condition, counting cells, adding 100 μ L of culture medium mixed with cells into each well, and controlling density at 5 × 10 per well 3 PBS is added in the outermost circle to prevent solvent evaporation, only the middle 60 holes are used, and a blank control group (culture medium), a negative control group (culture medium + cells) and an experimental group (culture medium + cells + compounds) are simultaneously arranged, and 3 auxiliary holes are arranged in each group of experiments.
(2) And (3) cell culture: the cells are cultured in a carbon dioxide constant temperature incubator overnight, different cells have special culture media, the concentration of the general compound is provided with five concentration gradients according to a twofold method, and each group of concentration has three auxiliary holes to ensure the accuracy of the result.
(3) Different concentrations of compounds were added and incubation continued for 24 h.
(4) The cells were added with MTT (5mg/mL) at a concentration previously prepared, incubated in an incubator for 4h, the medium was discarded, 150. mu.L of DMSO was added, and the mixture was placed on a shaker and shaken slowly for 10 min.
(5) Measurement of OD value: the microplate reader wavelength was set at 492 nm.
The experimental result shows that the compound has better safety when being incubated with RAW264.7 for 24 hours at the concentration of 20 mu M. The results are shown in FIG. 1.
2. Griess experiment
The Griess method is adopted to detect the inhibition effect of all compounds on the generation of NO induced by LPS, and the anti-inflammatory activity of the compounds can be reflected to a certain extent.
(1) RAW264.7 cells in log phase were collected, counted and plated on 48-well plates with 300. mu.L of medium added per well to give a cell density of about 7X 10 cells per well 4 And incubating overnight in a carbon dioxide constant temperature incubator.
(2) After overnight, five concentration gradients (1.25, 2.5, 5, 10, 20 μ M) of drug were added to the experimental groups and the blank and control groups were replaced with 300 μ L of fresh medium.
(3) The incubator was incubated for 1h and LPS (0.5. mu.g/mL) was added for 24h of incubation.
(4) Collecting cell supernatant, and centrifuging to detect.
(5) The Griess Reagent I and II were removed and the temperature was allowed to reach room temperature conditions.
(6) A50. mu.L/well aliquot of Griess Reagent I at room temperature was added to each well. Subsequently, an equal volume of Griess Reagent 4I was added as before. Note that this step is performed in the dark.
(7) And measuring the absorbance at 540nm by using a microplate reader, substituting the absorbance into a standard curve, and calculating the inhibition rate of each compound on NO secretion.
At a concentration of 10 μ M, compounds D3, D7, D20, D22, D23, D26, D38 had a strong inhibitory effect on NO release from RAW264.7, and the results are shown in fig. 2.
Further, the method can be used for preparing a novel materialThe compounds were tested for their anti-NO secretion activity and safety and the results are shown in Table 2. IC of Compounds on RAW264.7 cells 50 The values are all larger than 50 mu M, which indicates that the compound has better safety; at the same time, the anti-NO-secretion IC of the compounds D7, D20, D22, D23, D26 and D38 was found 50 Values less than 10. mu.M, especially IC of Compound D20 50 The value is 3.72, and the anti-inflammatory potential is better.
TABLE 2
Figure BDA0003652550870000221
Figure BDA0003652550870000231
Figure BDA0003652550870000241
3. Elisa experiment
The inhibition effect of all compounds on IL-1 beta generation induced by LPS/Nigericin is detected by adopting an Elisa method, and the anti-inflammatory activity of the compounds can be reflected to a certain extent.
(1) Mature-inducing BMDMs cells were collected, counted and plated on 96-well plates with 100. mu.L of medium added per well to give a cell density of about 1X 10 per well 5 And incubating overnight in a carbon dioxide incubator.
(2) After overnight culture, adding LPS (0.2 mu g/mL) for culture for 4h, adding the drug with five set concentration gradients (0.8, 4 and 20 mu M) into the experimental group for co-incubation for 1 h; cells were activated for 30min by the final addition of Nigericin (10. mu.M).
(3) Collecting cell supernatant, and centrifuging to detect.
(5) Detection was performed according to the ELISA kit instructions.
(6) Absorbance was measured at 450nm with a microplate reader, and the standard curve was substituted to calculate the IL-1. beta. secretion of each compound.
At a concentration of 20. mu.M, compounds D20, D22, D23, D26 and D38 showed strong inhibitory effect on IL-1. beta. release from RAW264.7, and the results are shown in FIG. 3.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, and such changes and modifications are within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (3)

1. The pterostilbene N-phenylamide compound is characterized by having a structure shown as a formula I:
Figure FDA0003652550860000011
wherein R is 1 Is methyl or propargyl; r 2 Is phenyl; r is 3 Is phenyl, substituted phenyl, thienyl, furyl, or C1-5 alkyl, substituted alkyl, cycloalkyl, alkenyl, ether group or ester group.
2. The method for preparing pterostilbene N-phenylamide compounds as claimed in claim 1, characterized in that: is prepared from pterostilbene and R 1 Reacting the intermediate A1-2 with the intermediate X, reacting the intermediate A1-2 with phosphorus oxychloride to obtain an intermediate B1-2, and reacting the intermediate B1-2 with the intermediate R 2 -NH 2 Reacting to obtain a compound C1-2, and reacting the intermediate C1-2 with R 3 -COCl reaction to give compound D1-41;
the synthetic route is as follows:
Figure FDA0003652550860000012
wherein R is 1 Is methyl or propargyl; r 2 Is phenyl; r 3 Is phenyl, substituted phenyl, thienyl, furyl or alkyl, substituted alkyl, cycloalkyl, alkenyl, ether group or ester group with 1-5 carbon atoms;
when R is 1 When is methyl, X is I; when R is 1 In the case of propargyl, X is Br.
3. The use of pterostilbene N-phenylamide compounds as claimed in claim 1 for the preparation of anti-inflammatory agents.
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Application publication date: 20220823