CN114573490A - diaryl-2H-aziridines and diaryl aziridines compounds, preparation method and application thereof - Google Patents
diaryl-2H-aziridines and diaryl aziridines compounds, preparation method and application thereof Download PDFInfo
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- CN114573490A CN114573490A CN202011386653.XA CN202011386653A CN114573490A CN 114573490 A CN114573490 A CN 114573490A CN 202011386653 A CN202011386653 A CN 202011386653A CN 114573490 A CN114573490 A CN 114573490A
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- trimethoxyphenyl
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
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Abstract
The invention belongs to the field of chemical pharmacy in the research and development of new drugs, and relates to novel chiral diaryl substituted-2H-aziridine compounds and diaryl substituted aziridine compounds with remarkable anti-tumor activity, a preparation method, in-vivo and in-vitro anti-tumor activity, acceptable pharmaceutical salts thereof, or application of a compound drug taking the compounds as one of the components in preparing drugs for preventing and treating tumor-related diseases. The compound or the pharmaceutically acceptable salt thereof provided by the invention can effectively inhibit the growth of transplanted tumor of nude mice in vitro and in vivo through a regulation mechanism of inhibiting tubulin aggregation to inhibit tumor cell proliferation, and can be applied to the preparation of medicaments for preventing or treating tumor-related diseases. The above-mentioned andtumor-related diseases include benign and malignant tumors and other diseases caused by tumors.
Description
Technical Field
The invention belongs to the field of chemical pharmacy in the research and development of new drugs, and relates to novel chiral diaryl substituted-2H-aziridine compounds and diaryl substituted aziridine compounds with remarkable anti-tumor activity, a preparation method, in-vivo and in-vitro anti-tumor activity, acceptable pharmaceutical salts thereof, or application of a compound drug taking the compounds as one of the components in preparing drugs for preventing and treating tumor-related diseases.
Background
At present, there are almost hundreds of approved antitumor drugs on the market, mainly including the following types: (1) DNA-acting antitumor drugs: such as alkylating agents, metal platinum complexes, DNA topoisomerase inhibitors, antimetabolite antitumor agents and the like; (2) kinase-acting antitumor drugs: such as tyrosine kinase inhibitors and serine/threonine kinase inhibitors; (3) antineoplastic drugs acting on microtubules (Microtubule): include microtubule aggregation inhibitors (i.e., microtubule destabilizers, represented by vinblastine, colchicine, podophyllotoxin, and Combretastatins) and microtubule aggregation promoters (i.e., microtubule stabilizing agents, represented by paclitaxel and epothilones).
The microtubule aggregation inhibitor not only has the ability of inhibiting Tubulin (Tubulin) polymerization, but also has the functions of specifically targeting and destroying generated tumor vessels and starving tumors aiming at the tumor vessels, and most of the drugs do not have multi-drug resistance, so the microtubule aggregation inhibitor becomes an anti-tumor drug which is researched more actively in recent years. The tubulin aggregation inhibitor Combretastatin (Combretastatin A-4, CA-4 for short) targeting colchicine binding site is a series of cis-stilbene natural products separated from the bark or stem of African bush short willow (combretaum caprunm) in 1982, has stronger activity of inhibiting tubulin aggregation and selectively inhibiting tumor angiogenesis, and has made a series of important progresses in the structural modification research. For example, chiral β -lactam CA-4 analogs with significant anti-tumor activity (J.Med.chem.2016,59, 10329-.
DNA alkylating agents play an important role in clinical chemotherapy of tumors, and are nitrogen mustard compounds which are one of the most widely used DNA crosslinking agents at the earliest time. The pharmacophore N, N-dichloroethylamine can be converted into a complex natural product such as reactive electrophilic aziridine, mitomycin C and the like through intramolecular conversion, and an aziridine structure also exists in the complex natural product, and a cross-linking structure is formed between the aziridine structure and DNA through the aziridine structure, so that the antitumor activity is exerted.
Because the pathogenesis and the regulation mechanism of the tumor are very complex, the single-target-point medicine is not ideal in effect. The multi-target drug can act on a plurality of sites of the regulation network at the same time, and compared with a single-target drug, the multi-target drug can obtain a better anti-tumor effect. Meanwhile, due to the synergistic effect, the multi-target medicament can use lower dosage, thereby reducing toxic and side effects. Therefore, multi-target drugs are favored in tumor treatment, and molecularly targeted drugs such as imatinib, sorafenib, lapatinib and the like are all multi-target drugs.
According to the structural characteristics of compounds acting on colchicine sites and DNA, the structures of the compounds are fused, a novel diaryl substituted ternary ring compound is designed and synthesized, and activity research shows that the compound has double effects on Tubulin and DNA, has excellent multiple tumor cell proliferation inhibition activity and in-vivo anti-tumor activity, and is an anti-tumor candidate compound with novel structure and unique mechanism.
Disclosure of Invention
The invention aims to provide a novel tubulin aggregation inhibitor and an angiogenesis inhibitor, and particularly relates to a novel diaryl substituted aza-tricyclic compound with remarkable anti-tumor activity, a preparation method thereof and application of the compound and pharmaceutical salts thereof or compound medicines taking the compound as a component in preparation of medicines for preventing and treating tumor-related diseases.
The invention provides diaryl substituted-2H-aziridine and diaryl substituted aziridine compounds with the following general structures or pharmaceutical salts thereof,
wherein R is1And R2Is taken from hydrogenAn atom, an alkyl group, a substituted alkyl group, an alkoxy group, an alkylthio group, an acyloxy group, a hydroxyl group, an amino group, an alkylamino group, an acylamino group, an aryl group, a heteroaryl group, a vinyl group, a halogen atom, a methoxycarbonyl group, an allyloxy group, an propargyloxy group, a sulfonyloxy group, a sulfonylamino group, or a combination of 2 to 3 of the same or different groups described above. R is selected from hydrogen atom, alkyl, substituted alkyl, alkoxy, alkylthio, acyloxy, hydroxyl, amino, aryl, heteroaryl, vinyl or acyl.
Preferred compounds in the present invention are:
the "pharmaceutically acceptable salt" in the present invention includes, specifically, salts with inorganic acids such as halogen acids, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, oxalic acid, malic acid, lactic acid and camphorsulfonic acid.
The invention also aims to provide application of the compounds or the pharmaceutically acceptable salts of the compounds and compositions containing the compounds or the salts of the compounds in preparing medicines for preventing or treating diseases related to tumors.
The tumor-related diseases include, but are not limited to, thyroid cancer, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, gastric cancer, lung cancer, liver cancer, melanoma, lymphoma, prostate cancer, bladder cancer, brain glioma, nasopharyngeal cancer, neuroendocrine cancer, undifferentiated carcinoma, interstitial sarcoma, choriocarcinoma, malignant hydatidiform mole, and malignant teratoma.
The invention provides and proves that the diaryl substituted aza-ternary ring compound with obvious anti-tumor effect or the pharmaceutically acceptable salt thereof has good inhibition effect on the growth of tumor in-vitro and in-vivo anti-tumor experiments by acting on a regulatory mechanism of Tubulin/DNA double-target point inhibition tumor cell growth.
Drawings
Figure 1, compound 8 inhibits microtubule self-assembly inhibition assay in vitro.
FIG. 2, immunofluorescent staining test the effect of Compound 8 on microtubule filamentous structures.
Figure 3, compound 8 in vitro inhibition of angiogenesis assay.
Fig. 4, compound 8 comet assay.
FIG. 5, Compound 8 upregulates expression of DNA Damage inducing factors
FIG. 6, experiment of inhibition of HeLa cell colony formation by Compound 8
Figure 7, effect of compound 8 on cell cycle.
Figure 8, effect of compound 8 on cycle-related protein expression.
Figure 9, compound 8 induced apoptosis assay.
Figure 10, effect of compound 8 on apoptosis-related protein expression.
Figure 11, liver microsomal stability of compound 8.
Figure 12, nude mouse transplantation tumor experiment of compound 8.
Detailed Description
The present invention is further illustrated by the following examples. These examples are intended only to further illustrate the invention and do not alter the scope of protection of the invention. The process for the preparation of the object compounds of the present invention can be further embodied by the following representative compound preparation processes:
EXAMPLE 1 Synthesis of the Compound 3- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (1)
According to the method of the reference literature (J.org.chem.2017,82: 3631-3638; org.Biomol.chem.2018,16: 4333-4337), the target compound 1 is synthesized according to the following route:
synthesis of 11- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (1c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 1a (621mg, 3mmol), 3-fluoro-4-methoxyboric acid 1b (1.02g, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under ice bath conditions, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) gave 850mg of (1c) as a white solid in 85% yield. mp 106.5-109.3 ℃.1HNMR(400MHz,CDCl3)δ7.81(d,J＝8.4Hz,1H),7.76(d,J＝11.9Hz,1H),7.00(t,J＝8.3Hz,1H),6.46(s,2H),4.16(s,2H),3.96(s,3H),3.84(s,6H),3.83(s,3H).13C NMR(150MHz,CDCl3)δ195.32,153.37,152.81,152.05,151.98,151.16,136.94,130.03,129.75,129.72,126.00,125.98,116.27,116.14,112.37,106.35,60.83,56.30,56.11,45.47.ESI-HRMS(m/z):calcd for C18H19FO5Na(M+Na+),357.1108；found,357.1119.
1.21 Synthesis of- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (1d)
1- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 1c (1.0g, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is raised to 50 ℃ for reaction, and the reaction is stopped by detecting with a TLC plate or LC/MS low-resolution mass spectrum until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 899mg of a white solid (1d) in 86% yield. mp 123.5-126.0 ℃.1HNMR(400MHz,CDCl3)δ7.43(d,J＝12.6Hz,1H),7.34(d,J＝7.6Hz,1H),6.91(t,J＝8.6Hz,1H),6.46(s,2H),4.10(s,2H),3.89(s,3H),3.80(d,J＝2.6Hz,9H).13C NMR(150MHz,CDCl3)δ156.16,153.34,152.99,151.36,148.68,148.61,136.58,131.90,128.65,128.61,122.71,114.16,114.03,112.90,105.40,60.85,56.20,56.08,31.97.ESI-HRMS(m/z):calcd for C18H20FNO5Na(M+Na+),372.1223；found,372.1228.
Synthesis of 33- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (1)
1- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (349mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, acetic anhydride (0.15mL, 1.5mmol) is slowly added dropwise under an ice bath condition, and the mixture is heated to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) with dichloromethane, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 1e, and directly putting into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 261mg of (1) as a yellow solid in 78% yield. mp 121.1-123.8 ℃.1H NMR(400MHz,CDCl3)δ7.66(d,J＝9.5Hz,2H),7.11(t,J＝7.9Hz,1H),6.34(s,2H),3.98(s,3H),3.81(s,9H),3.24(s,1H).13C NMR(150MHz,CDCl3)δ162.43,153.34,153.27,151.98,151.91,151.62,137.32,136.46,127.31,116.91,116.79,116.65,116.60,113.40,102.78,60.88,56.38,56.06,34.93.ESI-HRMS(m/z):calcd for C18H18FNO4Na(M+Na+),354.1118；found,354.1113.。
EXAMPLE 2 Synthesis of the Compound 3- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (2)
The invention synthesizes a target compound 2 according to the following route:
synthesis of 11- (4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (2c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 2a (621mg, 3mmol), 4-methoxyphenylboronic acid 2b (912mg, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by a TLC plate, adding saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw materials completely disappear, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet-method sample silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) gave 805mg of (2c) as a yellow solid in 85% yield. mp 84.9-87.5 ℃.1H NMR(400MHz,CDCl3)δ8.01(d,J＝8.5Hz,2H),6.94(d,J＝8.4Hz,2H),6.48(s,2H),4.18(s,2H),3.87(s,3H),3.83(s,9H).13C NMR(150MHz,CDCl3)δ196.20,163.62,153.29,136.80,130.92,130.52,129.57,113.83,106.40,60.83,56.09,55.50,45.46.ESI-HRMS(m/z):calcd for C18H20O5Na(M+Na+),339.1202；found,339.1199.
2.21 Synthesis of- (4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (2d)
Adding 1- (4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 2c (948mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) respectively, heating to 50 deg.C, and reactingDetection is carried out by TLC plate or LC/MS low resolution mass spectrum, and the reaction is stopped until the raw material disappears. Concentrating the reaction solution, carrying out wet loading silica gel column chromatography (200-300 meshes) for separation and purification, and eluting the solvent: petroleum ether-ethyl acetate (10:3) gave 814mg of (2d) as a yellow oil in 82% yield.1HNMR(600MHz,CDCl3)δ7.57(d,J＝8.9Hz,2H),6.87(d,J＝8.9Hz,2H),6.47(s,2H),4.12(s,2H),3.81(s,3H),3.80(s,3H),3.79(s,6H).13C NMR(150MHz,CDCl3)δ160.55,157.10,153.28,136.50,132.27,128.14,127.87,113.94,105.50,60.83,56.06,55.30,32.22.ESI-HRMS(m/z):calcd for C18H21NO5Na(M+Na+),354.1317；found,354.1313.
Synthesis of 33- (4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrindin (2)
1- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (331mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, acetic anhydride (0.15mL, 1.5mmol) is slowly added dropwise under an ice bath condition, and the mixture is heated to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 2e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 225mg of (2) as a yellow solid in 71% yield. mp 117.5-120.6 ℃.1HNMR(400MHz,CDCl3)δ7.86(d,J＝8.2Hz,2H),7.06(d,J＝8.2Hz,2H),6.35(s,2H),3.90(s,3H),3.81(s,3H),3.80(s,6H),3.21(s,1H).13C NMR(150MHz,CDCl3)δ163.58,162.38,153.29,137.15,137.02,131.91,116.28,114.81,102.75,60.87,56.05,55.58,34.41.ESI-HRMS(m/z):calcd for C18H19NO4Na(M+Na+),336.1212；found,336.1204.。
EXAMPLE 3 Synthesis of the Compound 3- (benzo [ d ] [1,3] dioxin-5-yl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (3)
The invention synthesizes a target compound 3 according to the following route:
synthesis of 11- (benzo [ d ] [1,3] dioxin-5-yl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (3c)
Mixing 3,4, 5-trimethoxy phenylacetonitrile 3a (621mg, 3mmol) and benzo [ d][1,3]Adding dioxin-5-boric acid 3b (996mg, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly dropwise adding trifluoroacetic acid (2.23mL, 30mmol) under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 752mg of a white solid (3c), yield 76%. mp 117.4-119.0 ℃.1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.1Hz,1H),7.48(s,1H),6.86(d,J＝8.1Hz,1H),6.46(s,2H),6.05(s,2H),4.15(s,2H),3.84(s,6H),3.83(s,3H).13C NMR(151MHz,CDCl3)δ195.71,153.32,151.94,148.27,136.85,131.34,130.34,124.99,108.34,107.94,106.35,101.92,60.84,56.10,45.54.ESI-HRMS(m/z):calcd for C18H18O6Na(M+Na+),353.0995；found,353.0996.
Synthesis of 21- (benzo [ d ] [1,3] dioxin-5-yl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (3d)
1- (benzo [ d ]) is reacted with][1,3]Dioxin-5-yl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 3c (990mg, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is increased to 50 ℃ for reaction, and the reaction is stopped when the raw materials disappear by detecting with a TLC plate or LC/MS low-resolution mass spectrum. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) gave 859mg of a white oil (3d) in 83% yield. mp 143.3-146.6 ℃.1HNMR(400MHz,CDCl3)δ7.17(s,1H),7.10(d,J＝7.9Hz,1H),6.78(d,J＝8.0Hz,1H),6.47(s,2H),5.97(s,2H),4.10(s,2H),3.80(s,9H).13C NMR(150MHz,CDCl3)δ157.04,153.30,148.68,147.96,136.54,132.12,129.81,120.91,108.15,106.62,105.45,101.34,60.84,56.09,32.30.ESI-HRMS(m/z):calcd for C18H19NO6Na(M+Na+),368.1104；found,368.1101.
Synthesis of 33- (benzo [ d ] [1,3] dioxin-5-yl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (3)
1- (benzo [ d ]) will react][1,3]Dioxin-5-yl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (345mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, acetic anhydride (0.15mL, 1.5mmol) is slowly added dropwise under an ice bath condition, and the mixture is heated to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 3e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring at 80 deg.C for 1 hr under nitrogen protection, detecting disappearance of the raw material by TLC plate, concentrating the reaction solution, adding water (15mL) to the reaction system, extracting the aqueous phase (3X 10mL) with dichloromethane, combining the organic phases, and saturatingWashing with common salt water, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying by wet-method silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 258mg of (3) as a yellow solid in 79% yield. mp 113.6-115.5 ℃.1H NMR(400MHz,CDCl3)δ7.40(s,2H),6.96(d,J＝7.1Hz,1H),6.34(s,2H),6.10(s,2H),3.81(s,9H),3.22(s,1H),1.65(s,2H).13C NMR(150MHz,CDCl3)δ162.73,153.30,152.01,148.59,137.22,136.71,126.38,117.82,109.04,108.69,102.76,102.09,60.87,56.05,34.93.ESI-HRMS(m/z):calcd for C18H17NO5Na(M+Na+),350.1004；found,350.0990.。
EXAMPLE 4 Synthesis of the compound 3- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (4)
The invention synthesizes a target compound 4 according to the following route:
synthesis of 11- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (4c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 4a (621mg, 3mmol), 3, 4-dimethoxyphenylboronic acid 4b (1.09g, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 820mg of a white solid (4c) in 79% yield. mp 151.2-156.1 ℃.1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.3Hz,1H),7.57(s,1H),6.90(d,J＝8.3Hz,1H),6.49(s,2H),4.19(s,2H),3.95(s,3H),3.93(s,3H),3.84(s,6H),3.83(s,3H).13C NMR(150MHz,CDCl3)δ196.25,153.44,153.32,149.11,136.85,130.58,129.72,123.44,110.61,110.00,106.36,60.84,56.10,55.97,45.37.ESI-HRMS(m/z):calcd for C19H22O6Na(M+Na+),369.1308；found,369.1302.
Synthesis of 21- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (4d)
1- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 4c (1.03g, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is raised to 50 ℃ for reaction, and the reaction is stopped when the raw materials disappear by detecting with a TLC plate or LC/MS low-resolution mass spectrometry. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 844mg of a white solid (4d) in 78% yield. mp 118.2-120.6 ℃.1HNMR(400MHz,CDCl3)δ7.88(s,1H),7.29(d,J＝1.9Hz,1H),7.15(dd,J＝8.4,2.0Hz,1H),6.83(d,J＝8.4Hz,1H),6.49(s,2H),4.12(s,2H),3.89(s,3H),3.88(s,3H),3.80(s,3H),3.80(s,6H).13C NMR(150MHz,CDCl3)δ157.15,153.29,150.21,148.90,136.49,132.44,128.36,119.72,110.60,108.92,105.46,60.85,56.07,55.89,55.84,32.10,29.33.ESI-HRMS(m/z):calcd for C19H23NO6Na(M+Na+),384.1416；found,384.1417.
Synthesis of 33- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (4)
1- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (361mg, 1mmol) was added to a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath conditions, and the mixture was warmed to room temperature for reaction. Detecting with TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the water phase with dichloromethane (3 vol)10mL), the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the obtained filtrate is concentrated to obtain a crude product 4e which is not further separated and purified and is directly put into the next reaction. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 257mg of (4) as a yellow solid in 75% yield. mp is 101.5-103.6 ℃.1HNMR(400MHz,CDCl3)δ7.48(d,J＝8.6Hz,1H),7.43(dd,J＝8.2,1.7Hz,1H),6.99(d,J＝8.3Hz,1H),6.36(s,2H),3.97(s,6H),3.82(s,3H),3.81(s,6H),3.24(s,1H).13C NMR(150MHz,CDCl3)δ162.81,153.32,153.26,149.69,137.23,136.92,124.83,116.41,111.06,110.91,102.85,60.89,56.18,56.16,56.07,34.97.ESI-HRMS(m/z):calcd for C19H21NO5Na(M+Na+),366.1317；found,366.1312.。
EXAMPLE 5 Synthesis of the Compound 3- (4-ethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (5)
The invention synthesizes a target compound 5 according to the following route:
synthesis of 11- (3, 4-dimethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (5c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 5a (621mg, 3mmol), 4-ethoxyphenylboronic acid 5b (996mg, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve the substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under an ice bath condition, heating to 80 ℃ to react 2 & lt & gtFor 3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 861mg of a yellow solid (5c), yield 87%. mp 99.6-101.1 deg.C.1H NMR(400MHz,CDCl3)δ7.99(d,J＝8.4Hz,2H),6.93(d,J＝8.4Hz,2H),6.48(s,2H),4.17(s,2H),4.10(q,J＝6.6Hz,2H),3.83(s,6H),3.82(s,3H),1.44(t,J＝6.8Hz,3H).13C NMR(150MHz,CDCl3)δ196.18,163.06,153.28,136.80,130.92,130.56,129.38,114.25,106.41,63.79,60.83,56.09,45.42,14.67.ESI-HRMS(m/z):calcd for C19H22O5Na(M+Na+),353.1359；found,353.1355.
5.2 Synthesis of 2- (3,4, 5-trimethoxyphenyl) -21- (4-ethoxyphenyl) -ethane-1-ketoxime (5d)
1- (4-ethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 5c (990mg, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is increased to 50 ℃ for reaction, and the reaction is stopped when the raw materials disappear by detection through a TLC plate or LC/MS low-resolution mass spectrometry. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 890mg of red solid (5d) in 86% yield. mp 112.1-115.3 ℃.1HNMR(400MHz,CDCl3)δ7.56(d,J＝8.6Hz,2H),6.86(d,J＝8.6Hz,2H),6.48(s,2H),4.13(s,2H),4.03(q,J＝7.0Hz,2H),3.80(s,3H),3.78(s,6H),1.41(t,J＝6.9Hz,3H).13C NMR(150MHz,CDCl3)δ159.94,157.04,153.25,136.44,132.28,127.91,127.84,114.45,105.47,63.50,60.83,56.05,32.26,14.75.ESI-HRMS(m/z):calcd for C19H23NO5Na(M+Na+),368.1468；found,368.1469.
Synthesis of 33- (4-ethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (5)
1- (4-ethoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (345mg, 1mmol) was charged into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath conditions, and the mixture was warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 5e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 245mg of (5) as a yellow solid in 75% yield. mp 99.8-102.1 deg.C.1HNMR(400MHz,CDCl3)δ7.84(d,J＝8.6Hz,2H),7.04(d,J＝8.6Hz,2H),6.35(s,2H),4.12(q,J＝6.9Hz,2H),3.81(s,3H),3.80(s,6H),3.20(s,1H),1.46(t,J＝6.9Hz,3H).13C NMR(150MHz,CDCl3)δ163.00,162.34,153.28,137.13,137.07,131.91,116.03,115.22,102.74,63.90,60.87,56.04,34.37,14.66.ESI-HRMS(m/z):calcd for C19H21NO4Na(M+Na+),350.1368；found,350.1364.。
EXAMPLE 6 Synthesis of the compound 3- (4-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (6)
The invention synthesizes a target compound 6 according to the following route:
6.6 Synthesis of 11- (4-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (6c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 6a (621mg, 3mmol), 4-methylbenzeneboronic acid 6b (816mg, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly dropwise adding trifluoroacetic acid (2.23mL, 30mmol) under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 756mg of a red solid (6c) in 84% yield. mp 86.4-89.5 ℃.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.2Hz,2H),7.27(d,J＝8.2Hz,2H),6.48(s,2H),4.20(s,2H),3.83(s,6H),3.82(s,3H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ197.28,153.29,144.16,136.83,134.06,130.30,129.38,128.73,106.45,60.83,56.09,45.62,21.68.ESI-HRMS(m/z):calcd for C18H20O4Na(M+Na+),323.1253；found,323.1251.
6.21 Synthesis of- (4-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (6d)
Adding 1- (4-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 6c (900mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 746mg, 79% yield, as a yellow solid (6 d). mp 124.1-126.9 ℃.1HNMR(400MHz,CDCl3)δ7.52(d,J＝8.2Hz,2H),7.16(d,J＝8.0Hz,2H),6.47(s,2H),4.14(s,2H),3.80(s,3H),3.78(s,6H),2.35(s,3H).13C NMR(150MHz,CDCl3)δ157.43,153.24,139.48,136.45,132.80,132.20,129.28,126.38,105.48,60.83,56.22,56.04,32.29,21.27.ESI-HRMS(m/z):calcd for C18H21NO4Na(M+Na+),338.1362；found,338.1360.
Synthesis of 33- (4-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (6)
1- (4-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (315mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, acetic anhydride (0.15mL, 1.5mmol) is slowly added dropwise under ice bath conditions, and the mixture is heated to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 6e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 216mg of (6) as a yellow solid in 73% yield. mp 79.8-82.6 ℃.1HNMR(400MHz,CDCl3)δ7.81(d,J＝7.9Hz,2H),7.37(d,J＝7.8Hz,2H),6.35(s,2H),3.81(s,3H),3.80(s,6H),3.23(s,1H),2.46(s,3H).13C NMR(150MHz,CDCl3)δ163.26,153.30,144.22,137.21,136.86,130.04,129.92,121.16,102.79,60.87,56.05,34.55,21.92.ESI-HRMS(m/z):calcd for C18H19NO3Na(M+Na+),320.1257；found,320.1250.。
EXAMPLE 7 Synthesis of the Compound 3- (4-methoxy-3-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (7)
The invention synthesizes a target compound 7 according to the following route:
7.11 Synthesis of- (4-methoxy-3-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (7c) 3,4, 5-trimethoxyphenylacetonitrile 7a (621mg, 3mmol), 4-methoxy-3-methylbenzeneboronic acid 7b (996mg, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) were added to Schlenk's tube (100mL), tetrahydrofuran (40mL) and water (10mL) were added to completely dissolve the substrate, nitrogen was replaced, trifluoroacetic acid (2.23mL, 30mmol) was slowly added dropwise under ice bath conditions, and the temperature was raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 811mg of red solid (7c) in 82% yield. mp83.4-86.2 ℃.1H NMR(400MHz,CDCl3)δ7.89(dd,J＝8.5,1.9Hz,1H),7.84(s,1H),6.85(d,J＝8.6Hz,1H),6.48(s,2H),4.17(s,2H),3.89(s,3H),3.84(s,6H),3.82(s,3H),2.25(s,3H).13C NMR(150MHz,CDCl3)δ196.47,161.92,153.27,136.77,131.19,130.69,129.06,128.84,126.94,109.25,106.41,60.83,56.08,55.55,45.40,16.32.ESI-HRMS(m/z):calcd for C19H22O5Na(M+Na+),353.1359；found,353.1353.
7.21 Synthesis of- (4-methoxy-3-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-one oxime (7d)
Adding 1- (4-methoxy-3-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 7c (990mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and performing wet-process silica gel column chromatography (20)0-300 mesh) separation and purification, eluent: petroleum ether-ethyl acetate (10:3) afforded 879mg of a yellow solid (7d) in 85% yield. mp 117.1-120.4 ℃.1HNMR(400MHz,CDCl3)δ7.46(s,1H),7.42(dd,J＝8.5,2.1Hz,1H),6.78(d,J＝8.5Hz,1H),6.49(s,2H),4.13(s,2H),3.83(s,3H),3.80(s,3H),3.79(s,6H),2.20(s,3H).13C NMR(150MHz,CDCl3)δ158.82,157.22,153.23,136.42,132.41,128.63,127.57,126.80,125.43,109.63,105.49,60.83,56.04,55.35,32.26,16.37.ESI-HRMS(m/z):calcd for C19H23NO5Na(M+Na+),368.1468；found,368.1459.
Synthesis of 33- (4-methoxy-3-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (7)
1- (4-methoxy-3-methylphenyl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (345mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, acetic anhydride (0.15mL, 1.5mmol) is slowly added dropwise under an ice bath condition, and the mixture is heated to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 7e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 238mg of (7) as a yellow solid in 73% yield. mp 96.6-98.8 ℃.1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.7Hz,1H),7.70(s,1H),6.96(d,J＝8.3Hz,1H),6.35(s,2H),3.92(s,3H),3.81(s,3H),3.81(s,6H),3.19(s,1H),2.27(s,3H).13C NMR(151MHz,CDCl3)δ162.36,161.83,153.28,137.22,137.10,131.98,129.91,128.08,115.64,110.21,102.75,60.87,56.05,55.61,34.37,16.18.ESI-HRMS(m/z):calcd for C19H21NO4Na(M+Na+),350.1362；found,350.1357.。
EXAMPLE 8 Synthesis of the Compound 2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-acrylne (8)
The target compound 8 is synthesized according to the following route:
8.12 Synthesis of- (3-fluoro-4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (8c) 4-methoxy-3-methylbenzeneacetonitrile 8a (495mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 8b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) were added to Schlenk's tube (100mL), tetrahydrofuran (40mL) and water (10mL) were added to completely dissolve the substrate, nitrogen was replaced, trifluoroacetic acid (2.23mL, 30mmol) was slowly added dropwise under ice bath conditions, and the temperature was raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 791mg of a white solid (8c) in 79% yield. mp125.3-127.8 ℃.1H NMR(400MHz,DMSO)δ7.33(s,2H),7.16-7.07(m,2H),7.04-7.02(m,1H),4.35(s,2H),3.85(s,6H),3.81(s,3H),3.74(s,3H).13C NMR(150MHz,DMSO)δ196.30,152.94,152.68,151.87,150.26,145.66,145.59,141.82,131.45,128.03,127.98,125.74,117.08,116.96,113.58,105.90,104.47,60.06,59.96,56.01,55.95,55.81,43.32.ESI-HRMS(m/z):calcd for C18H19FO5Na(M+Na+),357.1108；found,357.1112.
Synthesis of 22- (3-fluoro-4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (8d)
Adding 2- (3-fluoro-4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 8c (1.00g, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) respectively, heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 890mg of white solid (8d), yield 85%. mp 96.9-99.1 deg.C.1HNMR(400MHz,CDCl3)δ7.04(d,J＝12.2Hz,1H),6.97(d,J＝8.2Hz,1H),6.87(d,J＝9.1Hz,1H),6.84(s,2H),4.10(s,2H),3.85(d,J＝2.6Hz,6H),3.83(s,6H).13C NMR(150MHz,CDCl3)δ157.09,153.18,151.54,146.23,146.16,139.27,130.83,129.59,129.55,124.14,124.12,116.46,116.34,113.51,103.84,60.90,56.28,56.14,31.29.ESI-HRMS(m/z):calcd for C18H20FNO5Na(M+Na+),372.1217；found,372.1216.
8.32- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-acrylne (8) 2- (3-fluoro-4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (349mg, 1mmol) was charged into a 100mL eggplant-shaped flask, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath, and the mixture was allowed to warm to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 8e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring at 80 deg.C for 1 hr under nitrogen protection, detecting disappearance of raw material by TLC plate, concentrating the reaction solution, adding water (15mL) to the reaction system, extracting the aqueous phase (3X 10mL) with dichloromethane, combining the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and collecting the filtrateAnd (3) separating and purifying by wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 258mg of (8) as a yellow solid in 78% yield. mp 84.3-86.5 ℃.1HNMR(400MHz,CDCl3)δ7.12(s,1H),6.91(s,1H),6.90(d,J＝11.9Hz,1H),6.84(d,J＝11.9Hz,1H),3.95(s,3H),3.92(s,6H),3.87(s,3H),3.28(s,1H).13C NMR(150MHz,CDCl3)δ163.28,153.89,153.25,151.62,146.99,146.91,142.33,134.14,134.10,121.97,118.84,113.87,113.74,113.37,106.74,61.05,56.39,34.3.ESI-HRMS(m/z):calcd for C18H18FNO4Na(M+Na+),354.1112；found,354.1107.。
EXAMPLE 9 Synthesis of the Compound 2- (4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-acrylne (9)
The target compound 9 is synthesized according to the following route:
9.12 Synthesis of- (3-fluoro-4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (9c) 4-methoxy-3-methylbenzeneacetonitrile 9a (495mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 9b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) were added to Schlenk's tube (100mL), tetrahydrofuran (40mL) and water (10mL) were added to completely dissolve the substrate, nitrogen was replaced, trifluoroacetic acid (2.23mL, 30mmol) was slowly added dropwise under ice bath conditions, and the temperature was raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 786mg of a white solid (9c) in 83% yield. mp87.2-89.0 ℃.1H NMR(400MHz,CDCl3)δ7.26(s,2H),7.19(d,J＝8.2Hz,2H),6.87(d,J＝8.1Hz,2H),4.19(s,2H),3.90(s,3H),3.89(s,6H),3.78(s,3H).13C NMR(150MHz,CDCl3)δ196.76,158.55,153.00,142.52,131.71,130.27,126.76,114.20,106.20,60.93,56.24,55.25,44.72.ESI-HRMS(m/z):calcd for C18H20O5Na(M+Na+),339.1202；found,339.1198.
9.22 Synthesis of- (4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (9d)
2- (4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 9c (948mg, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is increased to 50 ℃ for reaction, and the reaction is stopped when the raw materials disappear by detecting with a TLC plate or LC/MS low-resolution mass spectrometry. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 715mg of a white solid (9d) in 72% yield. mp 123.4-125.3 ℃.1HNMR(400MHz,CDCl3)δ8.97(s,1H),7.19(d,J＝7.7Hz,2H),6.85(s,2H),6.81(d,J＝7.5Hz,2H),4.11(s,2H),3.84(s,3H),3.81(s,6H),3.76(s,3H).13C NMR(150MHz,CDCl3)δ158.16,157.62,153.10,139.08,131.14,129.53,128.65,114.08,103.90,60.88,56.10,55.24,31.41.ESI-HRMS(m/z):calcd for C18H21NO5Na(M+Na+),354.1311；found,354.1305.
Synthesis of 32- (4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (9)
2- (4-methoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (331mg, 1mmol) was put in a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath, and the mixture was warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 9e, and directly putting the crude product into the next reaction without further separation and purification. Will be provided withDissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 225mg of (9) as a yellow solid in 72% yield. mp 88.8-91.5 ℃.1HNMR(400MHz,CDCl3)δ7.14(s,2H),7.09(d,J＝7.8Hz,2H),6.84(d,J＝7.8Hz,2H),3.94(s,3H),3.91(s,6H),3.79(s,3H),3.32(s,1H).13C NMR(150MHz,CDCl3)δ163.80,159.04,153.84,142.11,132.89,127.38,119.38,113.87,106.64,61.04,56.38,55.33,34.84.ESI-HRMS(m/z):calcd for C18H19NO4Na(M+Na+),336.1206；found,336.1208.。
EXAMPLE 10 Synthesis of the Compound 2- (benzo [ d ] [1,3] dioxin-5-yl) -3- (3,4, 5-trimethoxyphenyl) -2H-acridin (10)
The target compound 10 is synthesized according to the following route:
synthesis of 12- (benzo [ d ] [1,3] dioxin-5-yl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (10c)
Benzo [ d ] benzene][1,3]Dioxin-5-yl acetonitrile 10a (483mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 10b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) are added into a Schlenk's tube (100mL), tetrahydrofuran (40mL) and water (10mL) are added to completely dissolve the substrate, nitrogen is replaced, trifluoroacetic acid (2.23mL, 30mmol) is slowly dropped under ice bath conditions, and the temperature is raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by TLC plate, adding saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material disappears completely, extracting the aqueous phase (3X 15mL) with ethyl acetate, combining the organic phases, washing with saturated brineWashing, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) gave 742mg of white solid (10c) in 75% yield. mp 98.9-101.1 deg.C.1H NMR(400MHz,CDCl3)δ7.26(s,2H),6.82–6.67(m,3H),5.94(s,2H),4.16(s,2H),3.91(s,3H),3.90(s,6H).13C NMR(150MHz,CDCl3)δ196.50,153.03,147.93,146.60,142.62,131.62,128.32,122.37,109.69,108.49,106.18,101.05,60.95,56.28,45.17.ESI-HRMS(m/z):calcd for C18H18O6Na(M+Na+),353.0995；found,353.0989.
Synthesis of 22- (benzo [ d ] [1,3] dioxin-5-yl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (10d)
2- (benzo [ d ]) is reacted with][1,3]Dioxin-5-yl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 10c (990mg, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is increased to 50 ℃ for reaction, a TLC plate or an LC/MS low-resolution mass spectrum is used for detection, and the reaction is stopped until the raw materials disappear. Concentrating the reaction solution, carrying out wet loading silica gel column chromatography (200-300 meshes) for separation and purification, and eluting the solvent: petroleum ether-ethyl acetate (10:3) gave 786mg of a white solid (10d) in 76% yield. mp 96.3-98.7 ℃.1HNMR(400MHz,CDCl3)δ8.17(s,1H),6.86(s,2H),6.78(s,1H),6.73(s,2H),5.91(s,2H),4.09(s,2H),3.85(s,3H),3.83(s,6H).13C NMR(150MHz,CDCl3)δ157.44,153.12,147.91,146.14,139.16,130.97,130.36,121.46,109.07,108.34,103.86,100.94,60.89,56.13,31.73.ESI-HRMS(m/z):calcd for C18H19NO6Na(M+Na+),368.1104；found,368.1109.
Synthesis of 32- (benzo [ d ] [1,3] dioxin-5-yl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (10)
2- (benzo [ d ]) is reacted with][1,3]Dioxin-5-yl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (345mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, and acetic anhydride is slowly dropped under an ice bath condition(0.15mL, 1.5mmol), warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 10e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 222mg of a yellow solid (10) in 68% yield. mp 89.2-91.5 ℃.1H NMR(400MHz,CDCl3)δ7.13(s,2H),6.73(m,2H),6.56(s,1H),5.93(s,2H),3.94(s,3H),3.92(s,6H),3.29(s,1H).13C NMR(150MHz,CDCl3)δ163.69,153.86,147.86,147.00,142.21,134.96,119.84,119.11,108.22,106.69,106.39,101.05,61.04,56.39,35.17.ESI-HRMS(m/z):calcd for C18H17NO5Na(M+Na+),350.0998；found,350.0991.。
EXAMPLE 11 Synthesis of the Compound 2- (3, 4-Dimethoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-acriline (11)
The invention synthesizes a target compound 11 according to the following route:
11.12 Synthesis of- (3, 4-dimethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (11c) 3, 4-dimethoxyphenylacetonitrile 11a (531mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 11b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) were added to Schlenk's tube (100mL), followed by tetrahydrofuran (40mL) and water (10mL)) And (3) completely dissolving the substrate, replacing nitrogen, slowly dropwise adding trifluoroacetic acid (2.23mL and 30mmol) under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 840mg of a white solid (11c) in 81% yield. mp92.5-93.5 ℃.1H NMR(400MHz,CDCl3)δ7.27(s,2H),6.83(s,2H),6.79(s,1H),4.20(s,2H),3.91(s,3H),3.90(s,6H),3.86(s,6H).13C NMR(150MHz,CDCl3)δ196.71,153.02,149.11,148.04,142.60,131.70,127.21,121.43,112.32,111.35,106.23,60.95,56.27,55.89,55.86,45.20.ESI-HRMS(m/z):calcd for C19H22O6Na(M+Na+),369.1308；found,369.1311.
11.22 Synthesis of- (3, 4-dimethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-one oxime (11d)
Adding 2- (3, 4-dimethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 11c (1.03g, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 898mg of a white solid (11d), yield 83%. mp 137.4-139.9 ℃.1HNMR(400MHz,CDCl3)δ8.73(s,1H),6.86(s,2H),6.83(s,1H),6.79(d,J＝5.6Hz,2H),4.12(s,2H),3.84(s,6H),3.81(s,9H).13C NMR(150MHz,CDCl3)δ157.58,153.11,149.06,147.65,139.13,131.22,129.16,120.49,111.86,111.28,103.93,60.89,56.12,55.88,55.81,31.86.ESI-HRMS(m/z):calcd for C19H23NO6Na(M+Na+),384.1417；found,384.1421.
Synthesis of 32- (3, 4-dimethoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (11)
2- (3, 4-dimethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (361mg, 1mmol) was added to a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath conditions, and the mixture was warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 11e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 264mg of (11) as a yellow solid in 77% yield. mp 121.5-124.7 ℃.1H NMR(400MHz,CDCl3)δ7.14(s,2H),6.82(d,J＝8.0Hz,1H),6.74(d,J＝7.7Hz,1H),6.66(s,1H),3.94(s,3H),3.92(s,6H),3.87(s,3H),3.84(s,3H),3.31(s,1H).13C NMR(150MHz,CDCl3)δ163.78,153.85,149.01,148.49,142.17,133.44,119.26,118.56,111.18,109.18,106.67,61.04,56.39,55.99,55.89,35.16.ESI-HRMS(m/z):calcd for C19H21NO5Na(M+Na+),366.1311；found,366.1312.。
EXAMPLE 12 Synthesis of the Compound 2- (4-ethoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (12)
The target compound 12 is synthesized according to the following route:
12.12 Synthesis of (4-ethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (12c)
Adding 4-ethoxyphenyl acetonitrile 12a (483mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 12b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve the substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under ice bath conditions, and heating to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 831mg of a white solid (12c) in 84% yield. mp 62.8-64.9 ℃.1H NMR(400MHz,CDCl3)δ7.26(s,2H),7.17(d,J＝7.6Hz,2H),6.86(d,J＝7.4Hz,2H),4.18(s,2H),4.01(q,J＝6.4Hz,2H),3.90(s,3H),3.89(s,6H),1.40(t,J＝6.9Hz,3H).13C NMR(150MHz,CDCl3)δ196.82,157.94,153.00,142.51,131.73,130.24,126.62,114.78,106.23,63.43,60.94,56.25,44.79,14.84.ESI-HRMS(m/z):calcd for C19H22O5Na(M+Na+),353.1359found,353.1357.
Synthesis of 22- (4-ethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (12d)
Adding 2- (4-ethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 12c (990mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 859mg of a white solid (12d), 85% yield. mp 148.0-150.3 ℃.1HNMR(400MHz,CDCl3)δ9.01(s,1H),7.18(d,J＝8.6Hz,2H),6.85(s,2H),6.80(d,J＝8.7Hz,2H),4.11(s,2H),3.98(q,J＝7.0Hz,2H),3.84(s,3H),3.80(s,6H),1.38(t,J＝7.0Hz,3H).13C NMR(150MHz,CDCl3)δ157.63,157.53,153.08,139.06,131.17,129.51,128.51,114.65,103.90,63.40,60.88,56.09,31.45,14.84.ESI-HRMS(m/z):calcd for C19H23NO5Na(M+Na+),368.1468；found,368.1469.
12.32 Synthesis of (4-ethoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (12) 2- (4-ethoxyphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (345mg, 1mmol) was charged in a 100mL eggplant-shaped flask, triethylamine (0.28mL, 2mmol) and dichloromethane (15mL) as a solvent were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath, and the mixture was allowed to warm to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 12e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 242mg of 74% yield of a yellow solid (12). mp 103.1-105.7 ℃.1HNMR(400MHz,CDCl3)δ7.14(s,2H),7.08(d,J＝8.6Hz,2H),6.83(d,J＝8.6Hz,2H),4.01(q,J＝7.0Hz,2H),3.94(s,3H),3.91(s,6H),3.31(s,1H),1.40(t,J＝7.0Hz,3H).13C NMR(150MHz,CDCl3)δ163.83,158.41,153.84,142.09,132.72,127.38,119.43,114.44,106.63,63.50,61.04,56.39,34.89,14.83.ESI-HRMS(m/z):calcd for C19H21NO4Na(M+Na+),350.1362；found,350.1354.。
EXAMPLE 13 Synthesis of the Compound 2- (4-methylphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (13)
The invention synthesizes a target compound 13 according to the following route:
13.12 Synthesis of (4-methylphenyl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (13c)
4-methylphenylacetonitrile 13a (393mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 13b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) are added into a Schlenk's tube (100mL), tetrahydrofuran (40mL) and water (10mL) are added to completely dissolve the substrate, nitrogen is replaced, trifluoroacetic acid (2.23mL, 30mmol) is slowly dropped under ice bath conditions, and the temperature is raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 783mg of a white solid (13c) in 87% yield. mp 75.1-76.3 deg.C.1H NMR(400MHz,CDCl3)δ7.26(s,2H),7.15(dd,J＝11.6,8.4Hz,4H),4.21(s,2H),3.90(s,3H),3.88(s,6H),2.32(s,3H).13C NMR(151MHz,CDCl3)δ196.66,152.99,142.51,136.55,131.71,129.48,129.11,106.24,60.93,56.24,45.28,21.07.ESI-HRMS(m/z):calcd for C18H20O4Na(M+Na+),323.1253；found,323.1247.
13.22 Synthesis of- (4-methylphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (13d)
Adding 2- (4-methylphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 13c (900mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL anhydrous methanol, adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) respectively, heating to 50 deg.C, and reactingDetection is carried out by TLC plate or LC/MS low resolution mass spectrum, and the reaction is stopped until the raw material disappears. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) gave 812mg of a clear colorless oil (13d) in 86% yield.1HNMR(400MHz,CDCl3)δ7.16(d,J＝8.0Hz,2H),7.08(d,J＝7.9Hz,2H),6.86(s,2H),4.14(s,2H),3.84(s,3H),3.81(s,6H),2.30(s,3H).13C NMR(150MHz,CDCl3)δ157.50,153.09,139.08,135.98,133.59,131.14,129.36,128.38,103.88,60.87,60.44,56.09,31.82,21.07,21.02,14.20.ESI-HRMS(m/z):calcd for C18H21NO4Na(M+Na+),338.1362；found,338.1360.
13.32 Synthesis of (4-methylphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (13) 2- (4-methylphenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (315mg, 1mmol) was charged in a 100mL eggplant-shaped flask, triethylamine (0.28mL, 2mmol) and dichloromethane (15mL) as a solvent were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice-bath conditions, and the mixture was allowed to warm to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 13e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) afforded 237mg of (13) as a yellow solid in 80% yield. mp 89.6-92.4 ℃.1HNMR(400MHz,CDCl3)δ7.14(s,2H),7.11(d,J＝8.0Hz,1H),7.06(d,J＝8.1Hz,1H),3.94(s,3H),3.91(s,6H),3.32(s,1H),2.33(s,3H).13C NMR(150MHz,CDCl3)δ163.44,153.83,142.13,137.84,136.92,129.05,126.18,119.28,106.70,61.04,56.38,35.08,21.14.ESI-HRMS(m/z):calcd for C18H19NO3Na(M+Na+),320.1257；found,320.1254.。
EXAMPLE 14 Synthesis of the Compound 2- (4-methylthiophenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (14)
The invention synthesizes a target compound 14 according to the following route:
14.12 Synthesis of (4-methylthiophenyl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (14c)
4-methylthiophenylacetonitrile 14a (489mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 14b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) were added to a Schlenk's tube (100mL), tetrahydrofuran (40mL) and water (10mL) were added to completely dissolve the substrate, nitrogen was replaced, trifluoroacetic acid (2.23mL, 30mmol) was slowly added dropwise under ice bath conditions, and the temperature was raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 866mg of a red solid (14c) in 87% yield. mp 104.0-106.8 ℃.1HNMR(400MHz,CDCl3)δ7.25(s,2H),7.21(q,J＝8.3Hz,4H),4.21(s,2H),3.91(s,3H),3.89(s,6H),2.47(s,3H).13C NMR(151MHz,CDCl3)δ196.33,153.03,142.64,137.04,131.61,131.54,129.77,127.01,106.19,60.95,56.27,44.99,15.92.ESI-HRMS(m/z):calcd for C18H20O4SNa(M+Na+),355.0974；found,355.0971.
14.22 Synthesis of- (4-methylthiophenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (14d)
Adding 2- (4-methylthiophenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 14c (996mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) afforded 822mg of a white solid (14d) in 79% yield. mp 95.6-98.9 ℃.1HNMR(400MHz,CDCl3)δ7.19(m,4H),6.84(s,2H),4.13(s,2H),3.84(s,3H),3.81(s,6H),2.45(s,3H).13C NMR(150MHz,CDCl3)δ157.24,153.13,139.19,136.31,133.59,130.94,129.02,127.10,103.87,60.89,56.12,31.68,16.02.ESI-HRMS(m/z):calcd for C18H21NO4SNa(M+Na+),370.1083；found,370.1081.
14.2 Synthesis of 32- (4-methylthiophenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (14)
2- (4-methylthiophenyl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketoxime (347mg, 1mmol) was charged in a 100mL eggplant-shaped flask, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice-bath conditions, and the mixture was warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 14e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) to give233mg of a yellow solid (14) was obtained, the yield was 71%. mp 84.7-86.0 ℃.1HNMR(400MHz,CDCl3)δ7.20(d,J＝8.3Hz,2H),7.13(s,2H),7.09(d,J＝8.3Hz,2H),3.94(s,3H),3.91(s,6H),3.31(s,1H),2.47(s,3H).13C NMR(150MHz,CDCl3)δ163.28,153.86,142.25,137.92,137.22,126.72,119.01,106.73,61.05,56.40,34.84,16.05.ESI-HRMS(m/z):calcd for C18H19NO3SNa(M+Na+),352.0977；found,352.0981.。
EXAMPLE 15 Synthesis of the Compound 3- (Naphthalen-2-yl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (15)
The invention synthesizes the target compound 15 according to the following route:
15.11 Synthesis of- (Naphthalen-1-yl) -2- (3,4, 5-trimethoxyphenyl) ethan-1-one (15c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 15a (621mg, 3mmol), 2-naphthylboronic acid 15b (1.03g, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) gave 849mg of a yellow oil (15c) in 84% yield.1HNMR(400MHz,CDCl3)δ8.55(s,1H),8.06(d,J＝8.6Hz,1H),7.96(d,J＝8.0Hz,1H),7.88(t,J＝8.9Hz,2H),7.58(m,2H),6.53(s,2H),4.35(s,2H),3.83(d,J＝3.7Hz,9H).13C NMR(150MHz,CDCl3)δ197.54,153.35,136.91,135.62,133.89,132.48,130.35,130.19,129.59,128.64,128.57,127.80,126.88,124.19,106.52,60.83,56.10,45.76.ESI-HRMS(m/z):calcdfor C21H21O4(M+H+),337.1434；found,337.1432.
15.21 Synthesis of- (Naphthalen-1-yl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (15d)
1- (naphthalene-1-yl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 15c (1.01g, 3mmol) is added into a 100mL eggplant-shaped bottle, 35mL of anhydrous methanol is added, hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) are respectively added, the temperature is increased to 50 ℃ for reaction, and the reaction is stopped when the raw materials disappear by detection through a TLC plate or LC/MS low-resolution mass spectrum. Concentrating the reaction solution, carrying out wet loading silica gel column chromatography (200-300 meshes) for separation and purification, and eluting the solvent: petroleum ether-ethyl acetate (10:3) gave 770mg of colorless oil (15d) in 73% yield.1HNMR(400MHz,CDCl3)δ8.04(s,1H),7.84(m,4H),7.55–7.44(m,2H),6.53(s,2H),4.27(s,2H),3.80(s,3H),3.78(s,6H).13C NMR(150MHz,CDCl3)δ157.54,153.32,136.52,133.70,133.05,132.98,132.19,128.50,128.27,127.65,126.82,126.49,126.45,123.65,105.48,105.00,60.83,56.22,56.06,32.11.ESI-HRMS(m/z):calcdfor C21H22NO4(M+H+),352.1543；found,352.1537.
Synthesis of 33- (naphthalen-2-yl) -2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (15)
1- (naphthalene-1-yl) -2- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (352mg, 1mmol) was added to a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath conditions, and the mixture was warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 15e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring at 80 deg.C for 1 hr under nitrogen protection, detecting by TLC plateConcentrating the reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by using dichloromethane, combining organic phases, washing the organic phases by using saturated saline solution, drying the organic phases by using anhydrous sodium sulfate, filtering the mixture, concentrating the obtained filtrate, and separating and purifying the concentrated filtrate by using a wet-method sample silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) gave 223mg of yellow oil (15) in 67% yield.1HNMR(400MHz,CDCl3)δ8.32(s,1H),8.03(q,J＝8.5Hz,2H),7.93(t,J＝6.9Hz,2H),7.60(m,2H),6.41(s,2H),3.82(s,3H),3.80(s,6H),3.35(s,1H).13C NMR(150MHz,CDCl3)δ191.09,163.79,153.64,153.36,137.32,136.67,135.62,132.84,132.05,129.39,129.08,128.75,128.11,127.23,124.56,121.23,106.70,102.87,60.87,56.05,35.05.ESI-HRMS(m/z):calcd for C21H20NO3(M+H+),334.1438；found,334.1435.。
EXAMPLE 16 Synthesis of the Compound 3-phenyl-2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (16)
The invention synthesizes a target compound 16 according to the following route:
synthesis of 11-phenyl-2- (3,4, 5-trimethoxyphenyl) ethan-1-one (16c)
Adding 3,4, 5-trimethoxyphenylacetonitrile 16a (621mg, 3mmol), phenylboronic acid 16b (732mg, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve the substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under ice bath conditions, and heating to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by using a TLC plate, adding a saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw material completely disappears, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet loading silica gel column chromatography (200-300 meshes), and eluting: petroleum productsEther-ethyl acetate (5:1) gave a yellow oil in 79% yield.1H NMR(400MHz,CDCl3)δ8.07–7.95(m,2H),7.56(d,J＝7.3Hz,1H),7.47(t,J＝7.5Hz,2H),6.48(s,2H),4.22(s,2H),3.83(s,6H),3.83(s,3H).13C NMR(150MHz,CDCl3)δ197.59,153.33,136.90,136.57,133.29,130.04,128.69,128.57,106.47,60.83,56.09,45.71.ESI-HRMS(m/z):calcd for C17H19O4(M+H+),287.1278；found,287.1275.
16.21 Synthesis of phenyl-2- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (16d)
Adding 1-phenyl-2- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 16c (861mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol) respectively, heating to 50 ℃ for reaction, detecting by TLC plate or LC/MS low-resolution mass spectrometry, and stopping reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) gave 697mg of yellow oil (16d) in 77% yield.1H NMR(400MHz,CDCl3)δ7.67–7.57(m,2H),7.36(s,3H),6.47(s,2H),4.15(s,2H),3.80(s,3H),3.78(s,6H).13C NMR(150MHz,CDCl3)δ157.50,153.25,136.49,135.68,132.03,129.39,128.56,126.51,105.49,60.83,56.04,32.39.ESI-HRMS(m/z):calcd for C17H20NO4(M+H+),302.1387；found,302.1385.
Synthesis of 33-phenyl-2- (3,4, 5-trimethoxyphenyl) -2H-aziridine (16)
1-phenyl-2- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (302mg, 1mmol) is added into a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) are added, acetic anhydride (0.15mL, 1.5mmol) is slowly added dropwise under an ice bath condition, and the mixture is heated to room temperature for reaction. Detecting with TLC plate or LC/MS low resolution mass spectrum until the material disappears, adding water (15mL) to quench reaction system, extracting water phase (3X 10mL) with dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering to obtain filtrateAfter concentration, crude product 16e is obtained, which is directly put into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) gave 181mg of a yellow oil (16) in 64% yield.1HNMR(400MHz,CDCl3)δ7.92(d,J＝7.0Hz,2H),7.66–7.48(m,3H),6.36(s,2H),3.82(s,3H),3.80(s,6H),3.26(s,1H).13C NMR(150MHz,CDCl3)δ163.80,153.32,137.29,136.61,133.29,129.88,129.29,124.00,102.81,60.86,56.05,34.79.ESI-HRMS(m/z):calcd for C17H18NO3(M+H+),284.1281；found,284.1279.。
EXAMPLE 17 Synthesis of the Compound 2- (Naphthalen-2-yl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (17)
The invention synthesizes a target compound 17 according to the following route:
synthesis of 12- (naphthalen-2-yl) -1- (3,4, 5-trimethoxyphenyl) ethan-1-one (17c)
Adding 2-naphthylacetonitrile 17a (501mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 17b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2' -bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) into a Schlenk tube (100mL), adding tetrahydrofuran (40mL) and water (10mL) to completely dissolve a substrate, replacing nitrogen, slowly adding trifluoroacetic acid (2.23mL, 30mmol) dropwise under an ice bath condition, and heating to 80 ℃ for reacting for 2-3 hours. Detecting the reaction by TLC plate, adding saturated sodium bicarbonate solution (30mL) to the reaction system to quench the reaction when the raw material disappears completely, extracting the aqueous phase (3X 15mL) with ethyl acetate, combining the organic phases, washing with saturated saline waterWashing, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) gave 836mg of a yellow oil (17c) in 83% yield.1HNMR(400MHz,CDCl3)δ7.80(m,3H),7.72(s,1H),7.50–7.42(m,2H),7.40(d,J＝8.4Hz,1H),7.30(s,1H),4.41(s,2H),3.89(s,3H),3.88(s,6H).13C NMR(150MHz,CDCl3)δ196.44,153.03,142.62,133.57,132.36,131.67,128.42,127.94,127.68,127.57,127.40,126.21,125.80,106.27,60.93,56.25,45.81.ESI-HRMS(m/z):calcd for C21H21O4(M+H+),337.1434；found,337.1432.
17.2 Synthesis of 22- (Naphthalen-2-yl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (17d)
Adding 2- (naphthalene-2-yl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 17c (1.01mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL of anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by a TLC plate or LC/MS low-resolution mass spectrometry, and stopping the reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) gave 834mg of a yellow oil (17d) in 79% yield.1HNMR(400MHz,CDCl3)δ7.74(m,4H),7.43(s,3H),6.90(s,2H),4.34(s,2H),3.82(s,3H),3.77(s,6H).13C NMR(150MHz,CDCl3)δ157.26,153.13,139.17,134.22,133.61,132.17,131.05,128.36,127.62,127.49,126.98,126.85,126.12,125.55,103.92,60.86,56.08,32.47.ESI-HRMS(m/z):calcd for C21H22NO4(M+H+),352.1543；found,352.1540.
Synthesis of 32- (naphthalen-2-yl) -3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (17)
2- (Naphthalen-2-yl) -1- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (352mg, 1mmol) was added to a 100mL eggplant-shaped bottle, triethylamine (0.28mL, 2mmol) and a solvent dichloromethane (15mL) were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice bath conditions, and the mixture was warmed to room temperature for reaction. Low resolution by TLC plate or LC/MSDetecting by mass spectrum until the raw materials disappear, adding water (15mL) into the reaction system to quench the reaction, extracting an aqueous phase (3X 10mL) by using dichloromethane, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain a crude product 17e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) gave 253mg of a yellow oil (17) in 76% yield.1HNMR(400MHz,CDCl3)δ7.86–7.72(m,3H),7.67(s,1H),7.45(d,J＝6.1Hz,2H),7.23(d,J＝8.5Hz,1H),7.17(s,2H),3.94(s,3H),3.90(s,6H),3.50(s,1H).13C NMR(150MHz,CDCl3)δ163.21,153.88,142.28,138.44,133.25,132.79,128.08,127.73,127.53,126.30,125.62,125.05,124.08,119.05,106.82,61.04,56.37,35.41.ESI-HRMS(m/z):calcd for C21H20NO3(M+H+),334.1438；found,334.1435.。
EXAMPLE 18 Synthesis of the Compound 2-phenyl-3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (18)
The invention synthesizes a target compound 18 according to the following route:
synthesis of 12-phenyl-1- (3,4, 5-trimethoxyphenyl) ethan-1-one (18c)
Phenylacetonitrile 18a (351mg, 3mmol), 3,4, 5-trimethoxyphenylboronic acid 18b (1.27g, 6mmol), palladium acetate (11mg, 5 mol%), 2 '-bipyridine (15mg, 10 mol%) and potassium fluoride (348mg, 6mmol) were added to Schlenk's tube (100mL), and tetrahydrofuran (40mL) and water (10mL) were added to completely dissolve the substrate, nitrogen was replaced, and ice was addedUnder the bath condition, trifluoroacetic acid (2.23mL, 30mmol) is slowly dropped, and the temperature is raised to 80 ℃ for reaction for 2-3 hours. Detecting the reaction by a TLC plate, adding saturated sodium bicarbonate solution (30mL) into the reaction system to quench the reaction when the raw materials completely disappear, extracting an aqueous phase (3X 15mL) by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using a wet-method sample silica gel column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 720mg of a white solid (18c), 84% yield.1HNMR(400MHz,CDCl3)δ7.33(t,J＝7.2Hz,2H),7.29–7.22(m,5H),4.25(s,2H),3.90(s,3H),3.88(s,6H).13C NMR(150MHz,CDCl3)δ196.45,153.01,142.57,134.84,131.69,129.27,128.76,126.94,106.24,60.93,56.24,45.65.ESI-HRMS(m/z):calcd for C17H19O4(M+H+),287.1278；found,287.1279.
18.22 Synthesis of phenyl-1- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (18d)
Adding 2-phenyl-1- (3,4, 5-trimethoxyphenyl) ethane-1-ketone 18c (861mg, 3mmol) into a 100mL eggplant-shaped bottle, adding 35mL anhydrous methanol, respectively adding hydroxylamine hydrochloride (310mg, 4.5mmol) and potassium carbonate (828mg, 6mmol), heating to 50 ℃ for reaction, detecting by TLC plate or LC/MS low-resolution mass spectrum, and stopping reaction until the raw materials disappear. Concentrating the reaction solution, and separating and purifying by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (10:3) gave 679mg of 75% yield as a yellow oil (18 d).1HNMR(400MHz,CDCl3)δ7.27(t,J＝4.6Hz,4H),7.20(dd,J＝8.2,4.0Hz,1H),6.85(s,2H),4.18(s,2H),3.84(s,3H),3.80(s,6H).13C NMR(150MHz,CDCl3)δ157.30,153.10,139.12,136.73,131.07,128.68,128.52,126.46,103.89,60.88,56.08,32.31.ESI-HRMS(m/z):calcd for C17H20NO4(M+H+),302.1387；found,302.1386.
Synthesis of 32-phenyl-3- (3,4, 5-trimethoxyphenyl) -2H-aziridine (18)
Adding 2-phenyl-1- (3,4, 5-trimethoxyphenyl) ethane-1-oxime (302mg, 1mmol) into a 100mL eggplant-shaped bottle, addingTriethylamine (0.28mL, 2mmol) and dichloromethane (15mL) as a solvent were added, acetic anhydride (0.15mL, 1.5mmol) was slowly added dropwise under ice-bath conditions, and the mixture was warmed to room temperature for reaction. Detecting by TLC plate or LC/MS low resolution mass spectrum until the raw material disappears, adding water (15mL) into the reaction system to quench the reaction, extracting the aqueous phase (3X 10mL) by dichloromethane, combining the organic phases, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to obtain crude product 18e, and directly putting the crude product into the next reaction without further separation and purification. Dissolving the crude product in DMF (10mL), adding cesium carbonate (276mg, 2mmol), stirring for 1 hour at 80 ℃ under the protection of nitrogen, detecting the disappearance of raw materials by a TLC plate, concentrating a reaction solution, adding water (15mL) into the reaction system, extracting an aqueous phase (3X 10mL) by dichloromethane, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, and separating and purifying the obtained filtrate by wet loading silica gel column chromatography (200-300 meshes), wherein an eluent: petroleum ether-ethyl acetate (5:1) gave 207mg of a yellow oil (18) in 73% yield.1HNMR(400MHz,CDCl3)δ7.34–7.21(m,3H),7.20–7.15(m,2H),7.14(s,2H),3.94(d,J＝1.6Hz,3H),3.90(d,J＝1.6Hz,6H),3.33(s,1H).13C NMR(150MHz,CDCl3)δ163.12,153.85,142.21,140.89,128.33,127.15,126.23,119.08,106.76,61.03,56.39,35.17.ESI-HRMS(m/z):calcd for C17H18NO3(M+H+),284.1281；found,284.1279.。
EXAMPLE 19 Synthesis of the Compound 2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -aziridine (19)
The invention synthesizes a target compound 19 according to the following route:
2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -2H-acrylne (115mg,0.345mmol) and sodium borohydride (50mg,1.39mmol) were added to a 25mL eggplant-shaped flask, tetrahydrofuran (5mL) was added, and the mixture was stirred at room temperature for two hours and the reaction was completed on a TLC plate. Concentrating the reaction solution to dryness, adding into eggplant-shaped bottleAdding water (5mL), extracting an aqueous phase (3X 5mL) by using dichloromethane, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (10:3) afforded 105mg of (19) as a yellow solid in 91% yield. mp 117.4-120.3 ℃.1H NMR(400MHz,CDCl3)δ6.99(dd,J＝12.4,1.8Hz,1H),6.91(d,J＝8.4Hz,1H),6.75(t,J＝8.5Hz,1H),6.39(s,2H),3.81(s,3H),3.76(s,3H),3.74(s,6H),3.50(q,J＝6.5Hz,2H).13C NMR(150MHz,CDCl3)δ152.65,151.06,146.36,146.29,136.67,132.06,129.81,129.77,123.58,123.56,115.86,115.74,112.73,104.73,60.80,56.21,55.96,39.90,39.17.ESI-HRMS(m/z):calcd for C18H20FNO4(M+H+),334.1449；found,334.1445.。
EXAMPLE 20 Synthesis of the Compound 2- (3-fluoro-4-methoxyphenyl) -1-methyl-3- (3,4, 5-trimethoxyphenyl) aziridine (20)
The target compound 20 is synthesized according to the following route:
2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) -aziridine (100mg,0.298mmol) was added to a 25mL eggplant-shaped flask, iodomethane (5mL) was added, and the mixture was stirred at room temperature for 3 hours, and the reaction was detected by TLC plate. Concentrating the reaction solution, separating and purifying by column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (2:1) afforded 84mg of a white solid (20), yield 81%. mp 110.6-112.8 ℃.1H NMR(400MHz,CDCl3)δ6.97(d,J＝12.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.75(t,J＝8.5Hz,1H),6.35(s,2H),3.81(s,3H),3.75(s,3H),3.73(s,6H),2.74(q,J＝6.5Hz,2H),2.68(s,3H).13C NMR(150MHz,CDCl3)δ152.67,151.08,146.30,146.22,136.60,131.97,129.68,129.64,123.47,115.82,115.69,112.79,104.63,60.80,56.25,55.95,50.54,49.70,47.77.ESI-HRMS(m/z):calcd for C19H22FNO4Na(M+Na+),370.1403；found,370.1425.。
EXAMPLE 21 test of Activity of target Compounds to inhibit human tumor cell proliferation in vitro
Five human tumor cell lines were cultured in Dulbecco's Modified Eagle Medium (DMEM): human ovarian cancer cell strain (A2780), human colon cancer cell strain (HCT-116), human lung adenocarcinoma cell strain (A549), human cervical cancer cell strain (HeLa) and human acute T lymphocyte leukemia cell strain (Jurkat), wherein the five cell lines are cultured at 37 ℃ and contain 5% CO2The culture was performed under the conditions of (1) containing 100 units/mL of penicillin G, 100. mu.g/mL of streptomycin and 10% (V/V) of fetal bovine serum. The in vitro antiproliferative activity of the compounds was tested by the MTT method and positive samples CA-4 and mitomycin C were used as controls. Briefly, cells were first seeded in 96-well plates (2.5X 10 per well) containing 100. mu.L of growth medium3Individual cells), after 24 hours incubation, the cells were treated with different concentrations of test compound, and after 48 hours incubation, 20 μ of LMTT solution (5mg/mL) was added to each well, followed by another 4 hours incubation at 37 ℃, suspension was discarded and dimethyl sulfoxide (150 μ L) was added to each well, and lysed with shaking for 10 minutes. The absorbance of each well was measured at a wavelength of 570nm using a micro-standard multi-well plate reader (Biotech ELX800), and the inhibition and IC were calculated using GraphPad Prism software (version 6.0)50The value is obtained. The results are shown in table 1:
TABLE 1 antitumor cell proliferation Activity in vitro (IC) of 2, 3-diaryl-2H-aziridines and 2, 3-diaryl-aziridines50/μM)
Example 22 inhibition of tubulin aggregation experiments: in vitro tubulin self-assembly assay
Purified porcine brain tubulin polymerization kit was purchased from cytosketon, usa and the test compound was obtained byTurbidimetry was used to evaluate the inhibition of microtubule aggregation in vitro. Tubulin aggregation buffer contained 100mM PIPES (pH 6.7), 10mM magnesium chloride, 1mM ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA), 1mM GTP, and 3.4M glycerol. Adding compounds to be tested with different concentrations into the buffer solution, and simultaneously taking colchicine as a positive control sample and taking dimethyl sulfoxide as a negative control sample. And then placing the processed tubulin sample in an environment at 37 ℃, using a light absorption microplate reader SpectraMax 190 spectrophotometer of Molecular Devices in USA to detect the absorbance of a system at 340nm, drawing an absorbance curve, and analyzing to obtain the aggregation inhibition activity of the compound on the tubulin. Plotting the graph according to absorbance (as shown in FIG. 1); the results show that the compound 8 can obviously inhibit the tubulin aggregation and IC503.3 μ M, more significant in inhibition than the positive control colchicine (as shown in Table 2);
TABLE 2 microtubule aggregation inhibiting Activity of Compound 8
Example 23 inhibition of tubulin aggregation experiments: immunofluorescence experiment for detecting tubulin morphology experiment
Human cervical cancer cells (HeLa) were seeded in 6-well plates and treated with varying concentrations of the preferred compound (100nm, 200nm) while using 0.1% dimethyl sulfoxide as negative control, CA-4(10nm) as positive control, 5% CO at 37 deg.C2After incubation for 24 hours under conditions, the medium was washed twice with PBS, the cells were fixed with methanol, and infiltrated with 0.1% Triton X-100 in PBS for 4 minutes. Cells were incubated for 1 hour in PBS solution containing 1% Bovine Serum Albumin (BSA) to block non-specific antibody binding. The cells were then incubated with monoclonal antibodies (anti-a-tubulin) for 4h at room temperature, stained with fluorescent antibodies, washed three times with PBS, and then the nuclei were labeled with 4', 6-diamidino-2-phenylindole (DAPI). Finally, the cells were washed three times with PBS, and the effect of the test compound on the tubulin filamentous structure was observed under a fluorescence microscope (OLYMPUS), and photographed and recordedResults of the experiment (as shown in fig. 2).
EXAMPLE 24 in vitro inhibition of angiogenesis assay
MatriGel was thawed at 4 ℃, Human Umbilical Vein Endothelial Cells (HUVEC) suspended in Dulbecco's Modified Eagle Medium (DMEM) were incubated at 37 ℃ for 30min before seeding in 96-well plates, and then the cells were treated with different concentrations of the preferred compound (75nm, 150nm) while using 0.1% dimethyl sulfoxide as a negative control at 37 ℃ with 5% CO2After incubation for 12h under the conditions, the capillary formation formed was observed and photographed under an inverted microscope (OLYMPUS) (as shown in fig. 3).
Example 25 basic Single-cell gel electrophoresis (comet assay)
The test kit is purchased from Trevigen company in USA, adopts alkaline comet assay to detect the damage effect of preferred compound on DNA, firstly washes the amplification culture of acute T lymphocyte leukemia cell (Jurkat) with RPMI-1640 complete culture medium, when the cell grows to logarithmic phase, adjusts the cell density to 1 × 105cells/mL. Jurkat cells were seeded into six well plates at 3mL per well. The cells were then treated with different concentrations of the preferred compounds (100nm, 200nm, 400nm) while using dimethyl sulfoxide as a negative control and mitomycin C (200nm) as a positive control, 5% CO at 37 deg.C2Respectively culturing for 48 hours under the condition, removing upper layer solution in the culture plate, washing cells for 2 times by using 2mL of PBS, adding pancreatin, after the cells are detached from the wall, adding 1mL of DMEM culture medium into a pore plate, slightly blowing and beating the cells to completely shed, sucking the cells into a 5mL centrifuge tube after the cells are uniformly blown and centrifuged (1000r/min for 3min), sucking supernatant after centrifugation, and washing the cells for two times by using PBS. The cell suspension was mixed with low melting agarose at 37 ℃ and immediately smeared onto comet assay slides using a pipette. The slide was cured at 4 ℃ for 10 minutes, immersed in the freshly prepared lysis buffer for 2 hours, removed from the lysis buffer, washed free of excess salt in distilled water and air dried. It was then immersed in freshly prepared alkaline DNA helicase (1mM EDTA,200mM NaOH) for 30 minutes and subjected to electrophoretic separation at 4 deg.C (25V, 15 min). After electrophoresis, the slides were placed in a plateThe slide is rinsed twice with deionized water, rinsed once with 70% ethanol to render the slide neutral, dried at 37 ℃ for 15 minutes, stained with 50-100 μ L acridine orange solution (EB) for 10min, and rinsed twice or more with deionized water. Microscopy using a fluorescence microscope (OLYMPOS BX51) as soon as possible after staining (as shown in fig. 4) resulted in fluorescence fading over time. All of the above procedures are performed in the dark to avoid additional DNA damage.
Example 26 in vitro detection of expression of DNA Damage inducing factors
HeLa cells in logarithmic growth phase were completely digested with trypsin and blown into single cell solution, counted and inoculated into 60mm diameter culture dishes each containing 1X 10 cells6And (4) cells. After 24 hours of incubation at 37 ℃ in 5% carbon dioxide, the cells were treated with different concentrations of the preferred compound 8(0.8 μm, 1.6 μm, 3.2 μm) while incubation was continued for 48 hours with dimethyl sulfoxide as a negative control. Then discarding the culture solution, washing with ice-cold PBS for three times, adding the cells into a centrifuge tube, centrifuging at low speed for 10 minutes, discarding the supernatant, collecting the cells, cracking with RIPA lysate to obtain a protein sample, quantitatively loading on polyacrylamide gel, performing electrophoresis (SDS-PAGE) and SDS-PAGE protein gel transfer membrane (PVDF membrane) at 100V voltage, and sealing the membrane. And then sequentially carrying out primary antibody incubation, primary antibody washing, secondary antibody incubation and secondary antibody washing. At the end of the incubation, a developed image was taken (as shown in FIG. 5).
Example 27 cell colony formation assay
HeLa cells in logarithmic growth phase were completely digested with trypsin and blown into single cell solution, counted and seeded in six-well plates with 1000 cells per well. After the cells were attached, the cells were treated with different concentrations of the preferred compound 8(0.5 μm, 1.0 μm, 2.0 μm, 4.0 μm, 8.0 μm) while using dimethyl sulfoxide as a negative control, cultured for 48 hours at 37 ℃ under 5% carbon dioxide, the medium was changed, after one week of further culture under the same conditions, the liquid was blotted, and the cells were subsequently covered with a layer of 2-3 mm ice-cold methanol. Cells were fixed for 15min at-20 ℃. The fixative was blotted dry, rinsed three times with PBS, stained with giemsa or with crystal violet, the stain was washed away with PBS, dried thoroughly, observed under a microscope for colony formation and counted (as shown in figure 6).
Example 28 in vitro cell G2/M phase arrest assay
HeLa cells in logarithmic growth phase were completely digested with trypsin and blown into single cell solution, counted and inoculated into 60mm diameter culture dishes each containing 1X 10 cells6And (4) cells. After 24 hours of incubation at 37 ℃ in 5% carbon dioxide, the cells were treated with different concentrations of the preferred compound 8(0.4 μm, 0.8 μm, 1.6 μm, 3.2 μm) while using dimethyl sulfoxide as a negative control, incubated for a further 12 hours, the liquid was blotted dry, and the cells were covered with 2-3 mm ice-cold 75% ethanol. The cells were fixed at-20 ℃. The fixative was blotted, rinsed three times with PBS, PBS containing RNaseA was added, followed by staining with Propidium Iodide (PI) for 30 minutes in the dark, detection with flow cytometry, and analysis of the assay results with software (as shown in figure 7).
Example 29 in vitro cell cycle-related regulatory protein assays
HeLa cells in logarithmic growth phase were completely digested with trypsin and blown into single cell solution, counted and inoculated into 60mm diameter culture dishes each containing 1X 10 cells6And (4) cells. After 24 hours of incubation at 37 ℃ in 5% carbon dioxide, the cells were treated with different concentrations of the preferred compound 8(0.8 μm, 1.6 μm, 3.2 μm) while using dimethyl sulfoxide as a negative control and incubation was continued for 48 hours. Then discarding the culture solution, washing with ice-cold PBS for three times, adding the cells into a centrifuge tube, centrifuging at low speed for 10 minutes, discarding the supernatant, collecting the cells, cracking with RIPA lysate to obtain a protein sample, quantitatively loading on polyacrylamide gel, performing electrophoresis (SDS-PAGE) and SDS-PAGE protein gel transfer membrane (PVDF membrane) at 100V voltage, and sealing the membrane. And then carrying out primary antibody incubation, primary antibody washing, secondary antibody incubation and secondary antibody washing in sequence. At the end of incubation, a developed image was taken (as shown in FIG. 8).
Example 30 in vitro apoptosis assay
HeLa cells in logarithmic growth phase were completely digested with trypsin and blown into single cell solution, counted and inoculated into 60mm diameter culture dishes each containing 1X 10 cells5And (4) cells. After 24 hours of incubation at 37 ℃ in 5% carbon dioxide, the cells were treated with different concentrations of the preferred compound 8(1 μm, 2 μm, 4 μm, 8 μm) while using dimethyl sulfoxide as a negative control and incubation was continued for 48 hours. Then, the culture solution is discarded, the cells are washed with ice-cold PBS for three times, the cells are added into a centrifuge tube and centrifuged at low speed for 10 minutes, the supernatant is discarded, the cells are collected, and then the cells are covered with a layer of 2-3 mm ice-cold 75% ethanol. The cells were fixed at-20 ℃. The fixative was blotted, rinsed three times with PBS, double stained with Annexin V-APC and 7-AAD in the dark, and analyzed for apoptosis using flow cytometry (as shown in FIG. 9).
Example 31 in vitro apoptosis-related protein assay
HeLa cells in logarithmic growth phase were completely digested with trypsin and blown into single cell solution, counted and inoculated into 60mm diameter culture dishes each containing 1X 10 cells6And (4) cells. After 24 hours of incubation at 37 ℃ in 5% carbon dioxide, the cells were treated with different concentrations of the preferred compound 8(0.8 μm, 1.6 μm, 3.2 μm) while incubation was continued for 48 hours with dimethyl sulfoxide as a negative control. Then, the culture solution is discarded, the cells are washed with ice-cold PBS for three times, the cells are added into a centrifuge tube and centrifuged at low speed for 10 minutes, the supernatant is discarded, the cells are collected, the cells are lysed with RIPA lysate to obtain a protein sample, the protein sample is quantitatively loaded on polyacrylamide gel, electrophoresis (SDS-PAGE) and SDS-PAGE protein gel transfer membrane (PVDF membrane) are carried out at 100V voltage, and the membrane is sealed. And then carrying out primary antibody incubation, primary antibody washing, secondary antibody incubation and secondary antibody washing in sequence. At the end of incubation, a developed image was taken (as shown in FIG. 10).
Example 32 in vitro liver microsome metabolic stability study
The preferred compound 8 was dissolved in dimethyl sulfoxide to prepare test solutions, while using CA-4, testosterone (substrate for the P4503A4 enzyme), diclofenac (substrate for the P4502C9 enzyme), and pralineRopatone (a substrate for the P4502D6 enzyme) was used as a positive control, added to a 96-well plate at 10. mu.l per well, and stored at 4 ℃. The mixture containing the test compound and liver microsomes was preincubated at 37 ℃ for 10 minutes. The micro-particle solution was added to all reaction plates at 80. mu.l per well, all reaction plates containing the compound and micro-particle mixture were incubated at 37 ℃ for 10 minutes, and then the reaction was stopped by adding acetonitrile (MeCN) at five time points of 5, 10, 20, 30, 60min, 300. mu.l per well. After quenching the reaction at the above five time points, the samples were sealed and shaken for 10 minutes, after which each sample was centrifuged at 4000 rpm for 20 minutes at 4 ℃, and 100 μ l of the supernatant was taken for detection by liquid chromatography mass spectrometry/mass spectrometry. The peak value of all tested compounds at the initial time (t 0min) was set as 100%, and the percentage of test compounds metabolized by liver microsomes at different metabolic times was converted to the percentage of residual content. In vitro half-life (t) was calculated using the linear regression slope of the percent remaining of the compound measured versus incubation time1/2) And other relevant data (as shown in fig. 11 and table 3).
TABLE 3 in vitro half-life of Compound 8
Example 33 study of tumor therapeutic Effect at animal level
The animal protocol was approved by the animal ethics committee of the college of medicine of the university of Compound Dan. We purchased 6-week-old female Balb/C nude mice from Shanghai Slek laboratory animals Co., Ltd, and implanted A2780 cells suspended in PBS to both subcutaneous sides of the mice to establish a nude mouse tumor metastasis model. When the tumor volume reaches 100mm3At the time, mice were randomly divided into four groups of ten mice each, and administered by intraperitoneal injection: various concentrations of 8(25mg/kg, 50mg/kg), colchicine (10m/kg) and blank (containing 10% castor oil and 10% dimethyl sulfoxide). Signs of intoxication and death were observed daily, mice were weighed each time and tumor volume (mm) was measured with a vernier caliper3) (pi/6) × length × width). When the tumor volume reached 2000mm3At that time, mice were sacrificed, tumors were isolated and weighed, and tumor inhibition rates were calculated (as shown in fig. 12).
Example 34 preliminary stability Studies
The 8(5mg/mL methanol, 20. mu.L) solution was mixed with phosphate buffer (480. mu.L, pH 7.4) and the resulting solution was filtered through a 0.22 μm microfiltration membrane. The filtrate was analyzed by HPLC (Poroshell 120 ec-C183.0X 50mm, 2.7 μm; mobile phase methanol/water 60:40, 1mL/min) at pH 7.4 after 4h, 8h, 12h, 24h and 48h, respectively. After 48h, the content of compound 8 in the pH 7.4 medium was found to be 95.77%.
EXAMPLE 35 enantiomeric resolution and specific optical rotation determination
Chiral resolution of enantiomer 8 was performed on a Thermo Fisher Ultimate 3000 HPLC using a Daicel Chiralpak IC chiral column with n-hexane/isopropanol (80/20) as the mobile phase at 1.0mL/min and UV response detected at 230nm wavelength at 25 ℃. Specific optical rotation data was measured using a Rudolph Autopol IV polarimeter at 25 ℃, using chloroform as the solvent and 1.0mg/mL sample concentration (as shown in table 4);
TABLE 4 in vitro antitumor Activity of enantiomers (IC)50/μM)
Example 36 Absolute configuration determination
Synthesis of Compound (2R,3S) -2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) aziridine (21)
The invention synthesizes a target compound 21 according to the following route:
compound 21a was obtained by chiral column resolution of compound 8 from (S) -3- (3-fluoro-4-methoxyphenyl) -2- (3,4, 5-trimethoxyphenyl) -2H-acrylne (115mg,0.345mmol) and sodium borohydride (50mg,1.39mmol) were addedTetrahydrofuran (5mL) was added to a 25mL round bottom flask, stirred at room temperature for two hours, and the reaction was completed as detected by TLC plate. Concentrating the reaction liquid to dryness, adding water (5mL) into an eggplant-shaped bottle, extracting an aqueous phase (3X 5mL) by using dichloromethane, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (10:3) gave 105mg of (21) as a yellow solid in 91% yield. mp 117.4-120.3 ℃.1H NMR(400MHz,CDCl3)δ6.99(dd,J＝12.4,1.8Hz,1H),6.91(d,J＝8.4Hz,1H),6.75(t,J＝8.5Hz,1H),6.39(s,2H),3.81(s,3H),3.76(s,3H),3.74(s,6H),3.50(q,J＝6.5Hz,2H).13C NMR(150MHz,CDCl3)δ152.65,151.06,146.36,146.29,136.67,132.06,129.81,129.77,123.58,123.56,115.86,115.74,112.73,104.73,60.80,56.21,55.96,39.90,39.17.ESI-HRMS(m/z):calcd for C18H20FNO4(M+H+),334.1449；found,334.1445.
Synthesis of Compound (2R,3S) -2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) aziridine (22)
The invention synthesizes the target compound 22 according to the following route:
(2R,3S) -2- (3-fluoro-4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) aziridine (20mg,0.06mmol), p-nitrobenzenesulfonyl chloride (20mg,0.09mmol), triethylamine (17. mu.L, 0.12mmol), and 4-dimethylaminopyridine (1mg,0.01mmol) were added to a 25mL eggplant-shaped flask, dichloromethane (3mL) was added, the mixture was stirred at room temperature for 1 hour, and the completion of the reaction was detected on a TLC plate. Concentrating the reaction liquid to dryness, adding water (5mL) into an eggplant-shaped bottle, extracting an aqueous phase (3X 5mL) by using dichloromethane, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate, separating and purifying by using column chromatography (200-300 meshes), and eluting: petroleum ether-ethyl acetate (5:1) afforded 27mg of (22) as a pale yellow solid in 87% yield. mp 133.1-134.2 ℃.1HNMR(400MHz,CDCl3)δ8.42(d,J＝8.9Hz,2H),8.27(d,J＝9.0Hz,2H),6.85–6.72(m,3H),6.22(s,2H),4.28–4.20(m,2H),3.80(s,3H),3.75(s,3H),3.65(s,6H).13C NMR(150MHz,CDCl3)δ153.06,152.72,151.08,150.83,147.70,147.63,143.69,138.03,129.29,126.38,124.52,124.11,124.07,123.70,115.59,115.46,113.08,104.84,60.82,56.19,56.02,48.34,47.44.ESI-HRMS(m/z):calcd for C24H23FN2O8S(M+Na+),541.1051；found,541.1050.
After the compound 22 is cultured on a single crystal, the configuration of the carbon atom at the 2-position of the target compound 22 is (R) -configuration and the configuration of the carbon atom at the 3-position is (S) -configuration through X-ray diffraction. It is concluded that (+) -8 is the (R) configuration.
Single crystals of22suitable for X-ray crystallographic analysis were obtained by slow evaporation ofa solution of22in petroleum ether/Dichloromethane.
TABLE 5 Crystal data and structure refinement for 22
Claims (6)
1. Diaryl substituted-2H-aziridine compounds, characterised by the general structure:
wherein R is1And R2Is selected from hydrogen atom, alkyl, substituted alkyl, alkoxy, alkylthio, acyloxy, hydroxyl, amino,Alkylamino, acylamino, aryl, heteroaryl, vinyl, halogen atoms, methoxycarbonyl, allyloxy, propargyloxy, sulfonyloxy, sulfonamido or a combination of 2 to 3 of the same or different groups as defined above.
2. Novel diaryl-substituted-2H-aziridines according to claim 1, as preferred compounds:
3. the diaryl substituted aziridine compound is characterized by having a structure shown in a general formula II:
wherein R is3And R4Is selected from hydrogen atom, alkyl, substituted alkyl, alkoxy, alkylthio, acyloxy, hydroxyl, amino, alkylamino, acylamino, aryl, heteroaryl, vinyl, halogen atom, methoxy formyl, allyloxy, propargyloxy, sulfonyloxy, sulfonylamino or combination of 2-3 of the same or different groups; r is selected from hydrogen, alkyl, substituted alkyl, hydroxyl, amino, aryl, heteroaryl, vinyl or acyl.
4. A novel diaryl substituted aziridine compound as claimed in claim 3, which is preferably a compound selected from the group consisting of:
5. use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the prevention and treatment of diseases associated with tumors, including interstitial sarcoma, choriocarcinoma, malignant hydatidiform mole, thyroid cancer, squamous cell carcinoma of the head and neck, cervical cancer, prostate cancer, renal cancer, bladder cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, gastric cancer, lung cancer, liver cancer, melanoma, lymphoma, brain glioma, nasopharyngeal cancer, neuroendocrine cancer, undifferentiated carcinoma, malignant teratoma, and benign tumor. Specific examples of the "pharmaceutically acceptable salt" include salts with organic acids such as malic acid, lactic acid, camphorsulfonic acid, citric acid, fumaric acid, and oxalic acid, and inorganic acids such as phosphoric acid, hydrohalic acid, sulfuric acid, and nitric acid.
6. A combination drug for the prevention and treatment of tumor-related diseases comprising the compound according to any one of claims 1 to 4, wherein the tumor-related diseases are thyroid cancer, lung cancer, liver cancer, melanoma, lymphoma, prostate cancer, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, undifferentiated carcinoma, interstitial sarcoma, choriocarcinoma, gastric cancer, bladder cancer, brain glioma, nasopharyngeal cancer, neuroendocrine cancer, malignant hydatidiform mole, malignant teratoma, and benign tumor.
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