A paclitaxel C(sp2)-H arylated derivative and its preparation method and application

Abstract

The present invention belongs to the field of biomedicine, and specifically relates to a C(sp2)-H arylated derivative of paclitaxel and a preparation method and application thereof. In the present invention, the ortho position of the benzene ring in the benzamide structure of the C-13 side chain of paclitaxel is C(sp 2 )-H activation, and substituted with aromatic compounds with structures such as amino acids, dipeptides, polypeptides, sugars, active drugs or fluorescein, to obtain new compounds including paclitaxel-peptide conjugates, paclitaxel-drug conjugates, paclitaxel-sugar conjugates and paclitaxel-fluorescein conjugates. After anti-tumor activity detection, it can be seen that the product of paclitaxel C(sp2)-H arylation still has certain anti-cancer activity, and the IC50 value of the product for target and non-target sites has a large difference, indicating that it has certain targeting selectivity.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically relates to a paclitaxel C(sp2)-H arylated derivative and a preparation method and application thereof. Background Art

[0002] Paclitaxel is a natural compound, a diterpene alkaloid compound, known as taxane or paclitaxel. It is extracted from the bark and leaves of the yew tree (Taxus brevifolia). Paclitaxel is an important anticancer drug and is widely used to treat a variety of cancers, especially breast cancer, ovarian cancer and lung cancer.

[0003] Paclitaxel works by inhibiting the division and growth of tumor cells. It can interfere with the normal division process of tumor cells, prevent the replication and separation of cell DNA, and thus inhibit the growth and spread of tumors. In addition, paclitaxel can also induce tumor cells to enter apoptosis (programmed cell death), further inhibiting the development of tumors.

[0004] Paclitaxel has high cytotoxicity but lacks cell selectivity. While killing cancer cells, paclitaxel also causes damage to normal cells and tissues, resulting in serious side effects in clinical applications, including bone marrow suppression, angioedema, hypotension, allergic reactions, systemic urticaria, sensory and central nervous system lesions, etc., which often make it difficult for cancer patients who need long-term medication to bear.

[0005] However, the shortcomings of paclitaxel, such as poor water solubility, low target selectivity, and multidrug resistance, have greatly limited its use in clinical drug therapy. In order to improve the pharmacological properties of paclitaxel, hydrophilic groups and bioactive groups are currently introduced into paclitaxel mainly through semi-synthesis and total synthesis, but the total yield of the product is extremely low. In addition, the strategy of terminal modification can be used to directly modify the 2′-OH, 7-OH and other sites of paclitaxel, but because the active sites of paclitaxel are occupied, the pharmacological activity test results of the modified paclitaxel analogs are not ideal. Summary of the invention

[0006] In view of the defect in the prior art that the 2′-OH, 7-OH and other sites of paclitaxel are modified to occupy the active site of paclitaxel, resulting in poor pharmacological activity test results of the modified paclitaxel analogs, the present invention provides a paclitaxel aryl derivative and a preparation method and application thereof to overcome the above defects. The specific technical scheme is as follows:

[0007] First, the present invention provides a paclitaxel C (sp 2 )-H arylated derivative, the structure of which is shown in formula (I):

[0008]

[0009] In formula (I), X includes one or more of amino acids, dipeptides, polypeptides, sugars, active drugs, and fluorescein.

[0010] Furthermore, the paclitaxel C(sp2)-H arylated derivative includes one or more compounds represented by the following formula:

[0011]

[0012]

[0013] In the present invention, the ortho position of the benzyl ring in the benzamide structure of the C-13 side chain of paclitaxel is C(sp 2 )-H activation, and substituted with aromatic compounds having structures such as amino acids, dipeptides, polypeptides, sugars, active drugs or fluorescein, to obtain new compounds including paclitaxel-peptide conjugates, paclitaxel-drug conjugates, paclitaxel-sugar conjugates and paclitaxel-fluorescein conjugates, and this position is an inactive site. Substitution at this position has a positive effect on the obtained paclitaxel C (sp 2 )-H arylation products have little effect on the pharmacological activity. 2 The anti-tumor activity of the )-H arylation products was detected. The results showed that the C(sp2)-H arylation products of paclitaxel still had certain anti-cancer activity, and the IC50 values ​​of the products for target and non-target sites were quite different, indicating that they had certain targeting selectivity.

[0014] Secondly, the present invention also provides a method for preparing a paclitaxel C(sp2)-H arylated derivative, wherein paclitaxel represented by formula (II) is used as a substrate, dissolved in a solvent, an aryl iodide represented by formula (III) is added, a catalyst, an additive, and an oxidant are added to react, and after the reaction is completed, the resulting mixture is post-treated to obtain a paclitaxel C(sp2)-H arylated derivative represented by formula (I) 2 )-H arylation derivatives:

[0015] CH activation is an atom-economical and simple chemical modification method, which is widely used in the later modification of various biologically active compounds. However, since paclitaxel contains multiple chiral centers and active groups, there are currently no reports on the modification of paclitaxel using CH activation.

[0016] The invention realizes the directional modification of the inactive site of paclitaxel by using the benzamide group in the natural internal skeleton of paclitaxel as the guiding group and the transition metal catalysis to carry out the directional C(sp2)-H arylation reaction. The inventor of the present application purposefully introduces iodinated aromatic hydrocarbon sources with different substituents to expand the substrate and successfully obtains a series of terminally modified paclitaxel arylation products, such as Ⅰa obtained by simple iodinated aromatic source modification, Ⅰb obtained by small molecule drug modification, Ⅰc obtained by sugar modification, Ⅰd obtained by fluorescent group modification, and Ⅰe and IF obtained by polypeptide modification. The reaction shows good substrate adaptability, and the one-step reaction in the invention directly obtains the product, which not only realizes the completion of the inactive site modification of paclitaxel at the designated position, but also avoids the step of introducing additional guiding groups and ligands. The method provided by the invention provides unlimited possibilities for improving the pharmacological properties of paclitaxel, so as to obtain paclitaxel candidate drugs with potential clinical application value, and provides effective experimental data for the clinical application of paclitaxel C(sp2)-H arylation products.

[0017] Furthermore, the catalyst is palladium acetate; the oxidant is silver acetate; and the additive is potassium fluoride.

[0018] CH activation reaction: This type of reaction is characterized by the use of palladium catalysis and the addition of oxidants. The metal is oxidized, and the metal is inserted into a specific carbon-hydrogen bond by relying on the directing group to form a metal hydride, which then undergoes further ligand exchange and reduction elimination to form a substitution product activated at a specific site.

[0019] Furthermore, the solvent is hexafluoroisopropanol.

[0020] Furthermore, the molar ratio of paclitaxel represented by formula (II), aryl iodide represented by formula (III), catalyst, oxidant and additive is 1-1.2:1-1.2:0.1-0.2:1-1.2:2.8-3.5.

[0021] Furthermore, the molar ratio of paclitaxel represented by formula (II), aryl iodide represented by formula (III), catalyst, oxidant and additive is preferably 1:1:0.1:1.2:3.

[0022] In the palladium-catalyzed CH activation reaction, the additive can not only stabilize the catalyst, but also promote the formation of metal coordination between the catalyst and the reaction substrate, so that the reaction catalytic system can be better circulated. In addition, the ligand provided by the preferred additive can enhance the selectivity of the reaction and accelerate the reaction rate.

[0023] Furthermore, the reaction is carried out at 70-110°C.

[0024] Furthermore, the reaction is preferably carried out at 100°C.

[0025] In this reaction, after the reaction temperature was raised to 120°C, more other impurities were produced and the reaction yield was reduced. After the reaction temperature was lowered to 80°C, the reaction efficiency deteriorated and the reaction yield was slightly reduced.

[0026] Furthermore, the concentration of the substrate in the solution is 0.05-0.1 mol / L.

[0027] Furthermore, the post-treatment is as follows: after the reaction mixture is cooled to room temperature, the reaction mixture is diluted with dichloromethane, and filtered through short diatomaceous earth, the filtrate is collected, the solvent is evaporated in vacuo, and further purified by column chromatography or preparative thin layer chromatography (PTLC) to obtain the final paclitaxel-containing C(sp2)-H arylated derivative shown in (I).

[0028] Finally, the present invention provides an application of a paclitaxel C(sp2)-H arylated derivative in the anti-tumor field, and an application of a paclitaxel C(sp2)-H arylated derivative as a fluorescent probe in targeting tumor microtubule proteins.

[0029] The present invention obtains a C(sp2)-H arylation derivative of paclitaxel by performing a C(sp2)-H arylation reaction at a specific site of paclitaxel. The reaction modifies the specific site of paclitaxel. By selecting the modification group, it is expected to prepare a paclitaxel derivative with strong anti-tumor activity and good cell selectivity. In the present invention, a paclitaxel C(sp2)-H arylation derivative with a tumor tubulin targeting function is obtained by coupling coumarin with fluorescent properties with paclitaxel.

[0030] Furthermore, the tumor is breast cancer, lung cancer, ovarian cancer, or human embryonic kidney cells.

[0031] The present invention has the following beneficial effects:

[0032] (1) The reaction of the present invention is to use the benzamide structure in the C-13 side chain of paclitaxel as a directing group and transition metal catalysis to achieve the reaction of paclitaxel C (sp 2 )-H arylation, which not only achieves the final modification of paclitaxel at the designated position, but also avoids the steps of introducing additional directing groups and ligands;

[0033] (2) The present invention provides a series of paclitaxel aromatic C(sp2)-H groups, which show good substrate adaptability;

[0034] (3) The method for modifying paclitaxel provided by the present invention provides unlimited possibilities for improving the pharmacological properties of paclitaxel and also provides a new direction for the terminal diversification of natural drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound Ia.

[0036] Figure 2 is the carbon NMR spectrum of compound Ia.

[0037] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound Ib.

[0038] Figure 4 is the carbon NMR spectrum of compound Ib.

[0039] Figure 5 is the hydrogen NMR spectrum of compound Ic.

[0040] Figure 6 is the carbon NMR spectrum of compound Ic.

[0041] Figure 7 is the hydrogen NMR spectrum of compound Id.

[0042] Figure 8 is the carbon NMR spectrum of compound Id.

[0043] Fig. 9 is the hydrogen NMR spectrum of compound 1e.

[0044] Fig.10 is the carbon NMR spectrum of compound 1e.

[0045] Fig.11 is the hydrogen nuclear magnetic resonance spectrum of compound If.

[0046] Fig.12 is the carbon NMR spectrum of compound If.

[0047] Fig.13 is the hydrogen nuclear magnetic resonance spectrum of compound Ig.

[0048] Fig.14 is the carbon NMR spectrum of compound Ig.

[0049] Fig.15 is the hydrogen nuclear magnetic resonance spectrum of compound 1h.

[0050] Fig.16 is the carbon NMR spectrum of compound Ih.

[0051] Fig.17 is the hydrogen nuclear magnetic resonance spectrum of compound Ii.

[0052] Fig.18 is the carbon NMR spectrum of compound Ii.

[0053] Fig.19 is the hydrogen nuclear magnetic resonance spectrum of compound Ij.

[0054] Fig. 20is the carbon NMR spectrum of compound Ij.

[0055] Fig.21 is the hydrogen nuclear magnetic resonance spectrum of compound Ik.

[0056] Fig. 22 is the carbon NMR spectrum of compound Ik.

[0057] Fig.23 is the hydrogen nuclear magnetic resonance spectrum of compound 11.

[0058] Fig.24 is the carbon NMR spectrum of compound 11.

[0059] Fig.25 Cell co-localization image of compound Ij. DETAILED DESCRIPTION

[0060] The present invention is further described below in conjunction with specific embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0061] Example 1: Preparation of compound (Ia):

[0062]

[0063] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence, the pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 h. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (ethyl acetate: petroleum ether = 5:2; Rf = 0.4) to obtain compound Ia (20.68 mg, yield 36%), and its nuclear magnetic resonance hydrogen spectrum can be found in Figure 1 , its carbon NMR spectrum can be found at Figure 2 .

[0064] 1H NMR(500MHz,DMSO-d6)δ8.85(d,J=9.2Hz,1H),8.00–7.95(m,2H),7.74–7.67(m,1H),7.61(t,J=7.6Hz,2H),7.50(td,J=7.3,2.0Hz,1H),7.47–7.40(m,2H),7.39–7.31(m,3H),7.24–7.18(m,3H),6.93(d,J=1.6Hz,2H),6.88(d,J=1.6Hz,1H),6.32(s,1H),6.11(d,J=7.3Hz,1H),5.90(t,J=9.4Hz,1H),5.44(d,J=7.2Hz,1H),5.30(dd,J=9.1,7.0Hz,1H),4.96(d,J=7.0Hz,1H),4.94–4.89(m,1H),4.76(s,1H),4.45(t,J=7.2Hz,1H),4.11(dt,J=10.8,6.9Hz,1H),4.02(q,J=8.2Hz,2H),3.62(d,J=7.1Hz,1H),2.32(ddd,J=15.4,10.3,7.2Hz,1H),2.22(s,4H),2.13(s,3H),2.09(s,6H),2.04(d,J=4.4Hz,1H),1.96–1.88(m,1H),1.80(d,J=1.4Hz,3H),1.71–1.60(m,2H),1.52(s,3H),1.05(s,6H)。

[0065] 13C NMR (151MHz, DMSO) δ202.93,173.20,170.29,169.28,169.23,165.70,140.38,139.91,139.82,139.16 ,137.58,137.32,133.89,133.82,130.42,130.29,130.04,129.94,129.18,129.03,128.67,128.43,1 27.77,127.72,127.28,126.61,84.07,80.75,77.20,75.83,75.30,74.98,74.27,70.95,70.23,57.93 ,56.05,46.59,43.47,37.02,35.10,26.77,22.92,21.75,21.22,21.17,14.35,10.24.HR-MS(ESI):m / z calcd for C55H59NO14[M+Na]+980.3828, found 980.3864.

[0066] Example 2: Preparation of compound (Ib):

[0067]

[0068] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1: 16; Rf = 0.4) to obtain compound Ib (21.33 mg, yield 31%), and its nuclear magnetic resonance hydrogen spectrum can be found in Figure 3 , its carbon NMR spectrum can be found at Figure 4 .

[0069] 1H NMR(500MHz,DMSO-d6)δ8.91(d,J=9.0Hz,1H),8.37(d,J=7.7Hz,1H),8.06(t,J=5.8Hz,1H),7.96(d,J=7.7Hz,2H),7.72(t,J=7.5Hz,1H),7.62(t,J=7.6Hz,2H),7.53–7.50(m,1H),7.43(dd,J=6.5,3.2Hz,3H),7.33(t,J=7.6Hz,2H),7.27(d,J=7.6Hz,2H),7.21(t,J=7.4Hz,1H),7.17(d,J=7.6Hz,2H),7.04(d,J=7.8Hz,2H),6.30(s,1H),6.14(d,J=7.4Hz,1H),5.88(t,J=9.3Hz,1H),5.42(d,J=7.3Hz,1H),5.24(t,J=8.2Hz,1H),4.96(d,J=7.0Hz,1H),4.90(d,J=9.6Hz,1H),4.73(s,1H),4.46(d,J=7.8Hz,2H),4.13–4.07(m,1H),4.01(q,J=8.5Hz,2H),3.70(d,J=5.9Hz,1H),3.66(d,J=5.8Hz,1H),3.61(s,6H),3.01(dd,J=13.9,5.5Hz,1H),2.88(dd,J=14.2,8.7Hz,1H),2.31(s,1H),2.19(s,3H),2.13(s,3H),1.84(s,3H),1.78(s,3H),1.50(s,3H),1.23(s,1H),1.03(s,6H)。

[0070] 13C NMR (126MHz, DMSO) δ185.84,178.00,177.14,175.08,174.92,174.45,174.13,174.08,170.48,145.00,144.54,144.48, 144.07,143.35,142.08,141.19,138.68,138.60,135.15,134.80,134.09,133.95,133.53,133.36,133.17,132.59,132 .15,127.70,125.67,123.21,122.00,112.97,112.90,85.50,84.41,84.15,83.88,81.96,80.05,79.73,62.69,61.04,5 8.63,58.49,57.16,51.34,48.21,46.83,41.55,39.82,33.63,31.53,27.63,25.91,19.07,14.98.HR-MS(ESI):m / zcalcd for C61H67N3O18[M+Na]+1152.4312, found1152.4312.

[0071] Example 3: Preparation of compound (Ic):

[0072]

[0073] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (ethyl acetate: petroleum ether = 5:1; Rf = 0.4) to obtain compound Ic (19.18 mg, yield 27%), and its nuclear magnetic resonance hydrogen spectrum can be found in Figure 5 , its carbon NMR spectrum can be found at Figure 6 .

[0074] 1H NMR(500MHz,DMSO-d6)δ8.87(d,J=9.0Hz,1H),8.46(d,J=7.3Hz,1H),7.99–7.95(m,2H),7.83(d,J=9.0Hz,1H),7.74–7.69(m,1H),7.62(t,J=7.7Hz,2H),7.51(ddd,J=7.6,5.6,3.3Hz,1H),7.44–7.41(m,2H),7.39(dd,J=7.5,1.0Hz,1H),7.33(t,J=7.6Hz,2H),7.26(d,J=8.1Hz,2H),7.21(t,J=7.4Hz,1H),7.17–7.14(m,2H),7.05(d,J=8.0Hz,2H),6.31(s,1H),6.10(d,J=7.4Hz,1H),5.89(t,J=9.0Hz,1H),5.43(d,J=7.2Hz,1H),5.28–5.23(m,1H),4.94(d,J=7.0Hz,1H),4.91(d,J=9.7Hz,1H),4.74(s,1H),4.46(q,J=8.0,7.6Hz,2H),4.22(dd,J=9.1,7.7Hz,1H),4.11(dt,J=11.5,7.0Hz,1H),4.01(q,J=8.1Hz,2H),3.61(d,J=7.2Hz,1H),3.58(s,3H),3.01(dd,J=14.1,5.9Hz,1H),2.92(d,J=8.9Hz,1H),2.31(q,J=6.1,5.7Hz,1H),2.20(s,3H),2.13(s,3H),1.90(d,J=13.6Hz,1H),1.82(s,3H),1.79(d,J=1.3Hz,3H),1.65(q,J=12.2,10.5Hz,3H),1.51(s,3H),1.42–1.30(m,2H),1.04(s,6H),0.82–0.78(m,6H)。

[0075] 13C NMR (151MHz, DMSO) δ202.91,173.21,172.29,171.93,170.30,169.54,169.30,169.28,165.71,162.81,139.80,139.37,139.02,138 .53,137.39,136.56,133.88,133.85,132.13,130.43,130.25,130.04,129.97,129.28,129.17,128.69,128.58,128.43,127.84,127 .70,127.35,84.09,80.76,77.21,75.84,75.30,74.99,74.11,70.94,70.19,57.94,56.92,56.19,55.36,53.81,52.21,46.60,43.4 7,37.12,37.02,36.59,36.26,35.11,31.25,26.80,24.68,22.93,22.91,21.74,21.16,15.60,14.33,11.40,10.24.HR-MS(ESI):m / z calcd for C65H75N3O18[M+Na]+1208.4938, found 1208.4936.

[0076] Example 4: Preparation of compound (Id):

[0077]

[0078] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (ethyl acetate: petroleum ether = 5:1; Rf = 0.4) to obtain compound Id (19.22 mg, yield 27%), and its nuclear magnetic resonance hydrogen spectrum can be found in Figure 7 , its carbon NMR spectrum can be found at Figure 8 .

[0079] 1H NMR(500MHz,DMSO-d6)δ8.87(d,J=9.0Hz,1H),8.41(d,J=8.1Hz,1H),8.01–7.93(m,2H),7.74–7.69(m,2H),7.64–7.59(m,2H),7.53–7.49(m,1H),7.43(dd,J=4.8,1.3Hz,2H),7.37–7.30(m,3H),7.27–7.23(m,2H),7.23–7.19(m,1H),7.18–7.14(m,2H),7.06(d,J=8.2Hz,2H),6.31(s,1H),6.09(d,J=7.5Hz,1H),5.89(t,J=9.0Hz,1H),5.43(d,J=7.1Hz,1H),5.28–5.22(m,1H),4.92(dd,J=16.1,8.2Hz,2H),4.73(s,1H),4.52(ddd,J=10.2,8.1,4.8Hz,1H),4.46(t,J=7.4Hz,1H),4.33(dd,J=9.3,5.6Hz,1H),4.11(dt,J=11.0,7.2Hz,1H),4.02(q,J=8.2Hz,2H),3.65(s,3H),3.61(d,J=7.1Hz,1H),3.06(dd,J=13.7,4.7Hz,1H),2.85(dd,J=13.7,10.3Hz,1H),2.37–2.25(m,1H),2.20(s,3H),2.13(s,3H),1.94–1.87(m,1H),1.86(s,3H),1.79(d,J=1.3Hz,3H),1.74(dd,J=15.3,9.0Hz,1H),1.64(t,J=12.7Hz,1H),1.58–1.54(m,1H),1.51(s,3H),1.27–1.21(m,1H),1.04(s,6H),0.93–0.85(m,1H),0.72(t,J=7.4Hz,3H),0.55(d,J=6.9Hz,3H)。

[0080] 13C NMR (151MHz, DMSO) δ202.91,174.36,173.22,172.49,171.91,170.29,169.76,169.29,168.46,165.71,164.03,143.38,139 .79,139.43,139.40,138.99,138.55,137.35,136.57,133.84,132.24,130.41,130.18,130.03,129.99,129.41,129.16,12 8.63,128.58,128.54,127.80,125.48,84.08,80.75,79.08,77.20,75.84,74.98,74.55,74.10,70.93,70.17,57.93,55.77 ,53.63,52.43,46.58,43.46,37.45,36.78,26.78,26.11,22.94,21.73,21.16,14.67,14.32,11.94,10.22.HR-MS(ESI):m / z calcd for C65H75N3O18[M+Na]+1208.4938, found 1208.4996.

[0081] Example 5: Preparation of compound (Ie):

[0082]

[0083] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1:15; Rf = 0.4) to obtain compound Ie (20.89 mg, yield 28%). Its nuclear magnetic resonance hydrogen spectrum can be found in Fig. 9 , its carbon NMR spectrum can be found at Fig.10 .

[0084] 1H NMR(500MHz,DMSO-d6)δ8.86(d,J=9.0Hz,1H),8.27–8.21(m,2H),8.06(d,J=7.5Hz,1H),7.98(d,J=1.3Hz,1H),7.73–7.69(m,1H),7.62(t,J=7.6Hz,2H),7.53–7.49(m,1H),7.46–7.40(m,3H),7.32(t,J=7.6Hz,2H),7.29–7.25(m,2H),7.21(t,J=7.3Hz,1H),7.17–7.13(m,2H),7.03(d,J=8.2Hz,2H),6.31(s,1H),6.09(d,J=7.5Hz,1H),5.89(t,J=9.1Hz,1H),5.43(d,J=7.2Hz,1H),5.26(t,J=8.1Hz,1H),4.92(dd,J=16.4,8.3Hz,2H),4.73(s,1H),4.50–4.40(m,2H),4.26–4.21(m,1H),4.11(dt,J=10.7,6.9Hz,1H),4.02(q,J=8.3Hz,2H),3.75(dd,J=16.8,6.1Hz,1H),3.66–3.62(m,1H),3.61(s,3H),3.01(dd,J=14.2,5.9Hz,1H),2.34–2.28(m,1H),2.20(s,3H),2.13(s,3H),1.91(dd,J=15.6,9.0Hz,1H),1.83–1.77(m,6H),1.77–1.72(m,1H),1.70–1.54(m,3H),1.51(s,3H),1.44(t,J=6.8Hz,2H),1.05(s,6H),0.85(dd,J=21.1,6.6Hz,8H)。

[0085] 13C NMR (151MHz, DMSO) δ202.90,173.23,173.06,172.32,170.29,170.13,169.42,169.30,169.27,165.70,139.78,139.32,138.98,13 8.57,137.38,136.49,133.85,130.43,130.30,130.03,129.98,129.28,129.17,128.76,128.57,128.42,127.92,127.82,127.71,1 27.37,84.08,80.76,77.20,75.84,75.29,74.98,74.12,70.94,70.18,57.93,56.21,53.99,52.37,51.81,46.59,46.24,43.47,42. 10,41.03,37.01,36.84,35.09,28.61,26.79,24.63,23.42,22.93,22.08,21.74,21.16,14.32,10.23,9.16.HR-MS(ESI):m / zcalcd for C67H78N4O19[M+Na]+1265.5152,found1265.5122.

[0086] Example 6: Preparation of Compound (IF):

[0087]

[0088] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1:15; Rf = 0.4) to obtain compound If (18.44 mg, yield 25%). Its nuclear magnetic resonance hydrogen spectrum can be found in Fig.11 , its carbon NMR spectrum can be found at Fig.12 .

[0089] 1H NMR(500MHz,Chloroform-d)δ8.14–8.10(m,2H),7.64–7.58(m,2H),7.50–7.45(m,3H),7.39–7.35(m,2H),7.35–7.29(m,5H),7.26(d,J=8.0Hz,2H),7.18(d,J=7.8Hz,2H),7.07(d,J=8.9Hz,1H),6.84–6.75(m,2H),6.69(d,J=8.5Hz,1H),6.27(s,1H),6.22(t,J=8.9Hz,1H),5.70(d,J=7.1Hz,1H),5.46(dd,J=8.4,3.5Hz,1H),4.94(dd,J=7.6,3.5Hz,2H),4.47(d,J=3.5Hz,1H),4.40(dd,J=11.0,6.6Hz,1H),4.27(d,J=8.5Hz,1H),4.19(dd,J=18.4,8.7Hz,2H),3.93(dd,J=17.1,6.0Hz,1H),3.75(s,4H),3.56(dd,J=17.0,4.9Hz,1H),3.25(dd,J=13.8,4.1Hz,1H),2.92(dd,J=13.8,9.1Hz,1H),2.54(ddd,J=14.6,9.7,6.6Hz,1H),2.31(s,3H),2.28(dd,J=9.1,5.4Hz,2H),2.25(s,3H),1.91–1.89(m,1H),1.87(s,3H),1.81(q,J=6.8Hz,3H),1.74(d,J=1.4Hz,3H),1.69(s,3H),1.16(s,3H),0.91–0.86(m,4H),0.82(dd,J=6.7,2.6Hz,6H)。

[0090] 13C NMR(151MHz,DMSO)δ202.92,173.22,172.28,172.00,171.58,171.40,171.12, 170.30,170.16,170.10,169.32,169.29,165.71,139.79,139.33,138.99,138. 56,137.38,137.33,136.47,133.90,133.85,131.88,131.71,130.41,130.02,129.24,129.17,128.73,128.59,128.40,127.84,127.37,119.65,92.88,84.07 ,80.75,77.20,75.83,75.28,74.97,74.11,70.94,70.17,57.95,57.93,57.80,57.50,56.21,53.94,53.40,52.31,52.23,46.58,43.46,42.47,42.43,37.00, 36.60,36.37,35.08,31.24,31.13,31.03,26.78,22.93,22.88,22.85,21.73,2 1.16,19.55,19.51,19.44,18.75,18.48,18.21,14.32,10.22.HR-MS(ESI):m / z calcd for C66H76N4O19[M+Na]+1251.4996, found 1251.4946.

[0091] Example 7: Preparation of Compound (Ig):

[0092]

[0093] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00 HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1:15; Rf = 0.4) to obtain compound Ⅰg (24.95 mg, yield 35%). Its nuclear magnetic resonance hydrogen spectrum can be found in Fig.13, its carbon NMR spectrum can be found at Fig.14 .

[0094] 1 H NMR (500MHz, DMSO-d6) δ10.86(s,1H),10.26(s,1H),8.88(d,J=8.9Hz,1H),7.96–7.93(m,3H),7.85(dt,J =7.9,1.4Hz,1H),7.78(d,J=8.6Hz,2H),7.71(ddd,J=8.3,4.9,2.6Hz,1H),7.69–7.66(m,1H),7.60–7.55 (m,3H),7.49(q,J=3.4,3.0Hz,4H),7.27(ddd,J=8.4,6.7,2.9Hz,5H),7.13(d,J=7.7Hz,2H),6.29(s,1H) ,6.12(dd,J=7.4,2.3Hz,1H),5.88(t,J=9.0Hz,1H),5.41(d,J=7.2Hz,1H),5.23(dd,J=8.8,7.2Hz,1H),4 .93(d,J=7.0Hz,1H),4.89(d,J=9.6Hz,1H),4.72(s,1H),4.47(t,J=7.3Hz,1H),4.22(t,J=6.6Hz,1H),4. 10(ddd,J=13.8,9.9,6.1Hz,1H),4.00(q,J=8.3Hz,2H),3.62–3.59(m,1H),2.36(d,J=8.4Hz,1H),2.31(t ,J=6.1Hz,1H),2.16(d,J=3.4Hz,3H),2.12(s,3H),1.78(d,J=1.4Hz,3H),1.66–1.60(m,2H),1.49(s,3H) ,1.37–1.33(m,1H),1.27(s,1H),1.23(s,2H),1.03(s,6H),0.91(t,J=7.4Hz,1H),0.76(t,J=7.4Hz,3H).

[0095] 13C NMR (126MHz, DMSO) δ186.86,181.50,172.85,172.84,171.00,169.82,165.24,162.38,153.73,152.46,142.59,142.37,139.32,138.48,1 38.12,134.87,134.15,133.42,132.80,128.70,128.20,127.20,126 .56,126.56,120.57,120.57,118.77,114.54,107.80,104.79,101.00 ,95.62,95.54,83.63,80.31,79.23,78.97,78.71,76.76,75.40,74. 53,71.72,70.55,67.53,61.35,57.49,49.89,43.01,42.27,41.39,40 .11,39.01,36.57,35.83,32.17,31.24,30.94,30.03,29.15,26.34,21.55,21.28,20.71,13.86,13.56,9.77,8.95,8.95.HR-MS(ESI):m / z calcd for C67H69N3O17[M+Na]+1210.4519,found1210.4573.

[0096] Example 8: Preparation of compound (Ih):

[0097]

[0098] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00-1.50 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence, the pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (ethyl acetate: petroleum ether = 3:2; Rf = 0.3) to obtain compound Ih (21.36 mg, yield 32%), and its nuclear magnetic resonance hydrogen spectrum can be found in Fig.15 , its carbon NMR spectrum can be found at Fig.16 .

[0099] 1H NMR(500MHz,DMSO-d6)δ8.89(d,J=8.9Hz,1H),7.97–7.95(m,2H),7.77–7.74(m,2H),7.72–7.68(m,1H),7.60(t,J=7.7Hz,2H),7.55(dd,J=7.4,1.7Hz,1H),7.52–7.47(m,2H),7.46(d,J=1.6Hz,2H),7.44(d,J=1.8Hz,1H),7.24(t,J=7.6Hz,2H),7.15–7.10(m,1H),7.06–7.03(m,2H),6.29(s,1H),6.14(d,J=7.4Hz,1H),5.89–5.84(m,1H),5.42(s,1H),5.22(dd,J=8.9,7.4Hz,1H),4.97(d,J=7.1Hz,1H),4.89(dd,J=9.5,2.2Hz,1H),4.84(dt,J=10.8,5.4Hz,1H),4.72(s,1H),4.42(t,J=7.4Hz,1H),4.09(dt,J=10.8,7.0Hz,1H),4.00(q,J=8.3Hz,2H),2.17(s,3H),2.12(s,3H),2.00(dd,J=16.3,4.0Hz,1H),1.91–1.85(m,2H),1.77(d,J=1.4Hz,3H),1.74–1.59(m,6H),1.56–1.53(m,1H),1.50(s,3H),1.23(d,J=7.6Hz,1H),1.11(t,J=11.5Hz,2H),1.03(s,6H),0.91–0.87(m,7H),0.77(d,J=6.9Hz,3H)。

[0100] 13C NMR (126MHz, DMSO) δ202.67,172.90,170.00,169.05,168.79,165.41,165.33,144.81,139.45,138.43,138.29,137.15,133.54,13 0.08,129.93,129.92,129.89,129.73,129.40,129.08,128.94,128.89,128.82,128.16,128.06,127.96,127.44,127.28,125.39,8 3.79,80.44,76.89,75.52,74.97,74.65,74.31,73.78,70.64,69.89,65.23,57.63,56.09,49.12,46.81,46.25,43.14,40.71,36.6 2,34.75,34.73,33.87,31.04,26.44,26.31,23.33,22.57,22.01,21.40,20.82,20.67,18.80,16.58,13.98,9.89.HR-MS(ESI):m / z calcd for C64H73NO16[M+Na]+1134.4822, found 1134.4879.

[0101] Example 9: Preparation of compound (Ii):

[0102]

[0103] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00-1.50 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence, the pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (ethyl acetate: petroleum ether = 3:2; Rf = 0.3) to obtain compound Ii (19.80 mg, yield 27%), and its nuclear magnetic resonance hydrogen spectrum can be found in Fig.17 , its carbon NMR spectrum can be found at Fig.18 .

[0104] 1H NMR(500MHz,DMSO-d6)δ8.95(d,J=9.0Hz,1H),7.97(d,J=1.2Hz,1H),7.96(d,J=1.6Hz,1H),7.81(d,J=8.5Hz,2H),7.73–7.69(m,1H),7.61(t,J=7.5Hz,2H),7.56(dd,J=7.4,1.8Hz,1H),7.51–7.46(m,5H),7.29(t,J=7.5Hz,2H),7.19–7.15(m,1H),7.14–7.11(m,2H),6.30(s,1H),6.15(d,J=7.4Hz,1H),5.92–5.83(m,1H),5.42(d,J=7.3Hz,1H),5.26–5.21(m,1H),4.94(d,J=7.1Hz,1H),4.92–4.88(m,1H),4.70(s,1H),4.67(dd,J=7.9,2.6Hz,1H),4.62(d,J=11.5Hz,1H),4.44–4.41(m,2H),4.31–4.28(m,1H),4.18(d,J=11.6Hz,1H),4.10(dt,J=13.7,6.9Hz,1H),4.04–3.98(m,2H),3.84–3.80(m,1H),3.67(d,J=12.9Hz,1H),3.60(d,J=7.2Hz,1H),2.35–2.29(m,1H),2.18(s,3H),2.13(s,3H),1.79(d,J=1.3Hz,3H),1.70(t,J=7.7Hz,1H),1.68–1.60(m,2H),1.51(s,3H),1.47(s,3H),1.37(s,3H),1.30(d,J=5.6Hz,6H),1.04(d,J=2.6Hz,6H)。

[0105] 13C NMR (151MHz, DMSO) δ202.87,173.18,170.27,169.26,168.92,165.68,165.46,145.33,139.74,138.84,138.45,133.86, 130.44,130.18,130.02,129.66,129.20,129.13,128.56,128.47,128.34,128.31,127.83,127.72,108.74,108.70,101. 45,84.16,84.06,80.75,77.19,75.82,75.27,74.98,74.13,70.93,70.52,70.11,69.76,65.61,61.14,57.92,56.35,55 .36,46.59,43.45,37.00,26.78,26.71,26.18,25.77,24.44,22.96,21.73,21.16,14.31,14.01,10.23.HR-MS(ESI):m / z calcd for C66H73NO21[M+Na]+1238.4567, found 1238.4524.

[0106] Example 10: Preparation of compound (Ij):

[0107]

[0108] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00-1.50 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence, the pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1: 21; Rf = 0.4) to obtain compound Ij (16.75 mg, yield 25%), and its nuclear magnetic resonance hydrogen spectrum can be found in Fig.19 , its carbon NMR spectrum can be found at Fig. 20 .

[0109] 1H NMR(500MHz,DMSO-d6)δ8.92(d,J=8.7Hz,1H),8.02–7.98(m,2H),7.97–7.94(m,1H),7.91–7.88(m,2H),7.76–7.71(m,1H),7.64(dt,J=12.8,7.6Hz,3H),7.58–7.54(m,1H),7.53–7.46(m,4H),7.43–7.39(m,5H),7.22(tt,J=5.9,2.7Hz,1H),6.63(s,1H),6.57(dd,J=8.6,2.2Hz,1H),6.41(d,J=2.2Hz,1H),5.93–5.87(m,2H),5.76(s,1H),5.50(d,J=7.5Hz,1H),5.44(t,J=8.1Hz,1H),5.03–4.94(m,2H),4.77(s,1H),4.62(d,J=7.5Hz,1H),4.27(d,J=8.4Hz,1H),4.16–4.11(m,2H),3.73(dd,J=6.9,4.6Hz,2H),2.35(s,3H),2.30(d,J=1.1Hz,2H),2.12(s,3H),1.75(dd,J=15.5,8.9Hz,1H),1.68(d,J=1.4Hz,2H),1.50(s,3H),1.23(s,3H),1.13(t,J=7.0Hz,3H),1.01(d,J=15.0Hz,6H)。

[0110] 13C NMR(151MHz,DMSO)δ207.90,185.70,173.02,171.92,169.39,167.79,166.74,1 65.81,163.61,161.22,155.93,154.23,154.13,153.53,139.79,139.51,134.94 ,133.98,133.50,133.33,131.83,131.22,130.50,130.03,130.00,129.73,129.25,129.03,128.76,127.87,126.67,113.73,111.66,109.33,107.94,104.76,9 9.01,93.93,82.08,81.88,78.16,77.50,77.10,75.64,75.55,74.17,69.95,67.45,67.34,57.30,56.74,55.36,45.68,44.55,42.79,40.89,35.57,35.51,35.4 1,34.14,31.75,29.67,29.45,29.16,29.01,27.70,26.47,26.26,24.96,23.05, 22.56,21.51,21.08,20.78,18.47,16.63,14.72,14.41,12.91.HR-MS(ESI):m / z calcd for C64H64N2O16[M+Na]+1139.4148,found1139.4167.

[0111] Example 11: Preparation of Compound (Ik):

[0112]

[0113] Paclitaxel II (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00-1.50 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence, the pressure tube was sealed, and then the reaction was placed at 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1: 10; Rf = 0.4) to obtain compound Ik (12.47 mg, yield 20%), and its nuclear magnetic resonance hydrogen spectrum can be found in Fig.21 , its carbon NMR spectrum can be found at Fig. 22 .

[0114] 1 H NMR (500MHz, Methanol-d4) δ8.12–8.06 (m, 2H), 7.70 (t, J = 7.4Hz, 1H), 7.62–7 .53(m,4H),7.49–7.35(m,6H),7.33–7.25(m,3H),7.21(d,J=7.9Hz,2H),6.45 (s,1H),6.13(t,J=9.0Hz,1H),5.64(d,J=7.1Hz,1H),5.43(d,J=6.1Hz,1H),5 .03–4.97(m,1H),4.60(d,J=6.1Hz,1H),4.32(dd,J=11.0,6.6Hz,1H),4.25(d d,J=8.4,5.0Hz,1H),4.19(d,J=3.5Hz,2H),3.81(d,J=7.1Hz,1H),3.33(p,J= 1.6Hz,8H),3.09(dd,J=14.5,8.3Hz,1H),2.48(ddd,J=15.5,9.6,6.7Hz,1H), 2.30(d,J=2.0Hz,3H),2.21(d,J=1.3Hz,3H),2.17–2.12(m,1H),1.92(d,J=1. 4Hz, 3H), 1.82 (dd, J = 14.3, 11.2Hz, 1H), 1.67 (s, 3H), 1.17 (d, J = 10.2Hz, 6H).

[0115] 13C NMR(151MHz,MeOD)δ203.83,173.00,171.40,170.40,170.08,166.29,161.76,140.72,139.72,139.62,13 5.78,133.61,133.55,133.28,130.01,129.94,129.76,129.22,128.98,128.35,127.92,127.69,127.29, 127.12,117.78,104.94,84.48,80.85,77.64,76.10,75.51,74.86,73.58,70.99,70.86,57.86,56.31,48 .48,48.06,46.47,43.21,36.10,35.67,35.12,25.57,21.89,20.95,19.44,13.37,9.04.HR-MS(ESI):m / z calcd forC56H60N2O16[M+Na]+1039.3835,found1039.3856.

[0116] Example 12: Preparation of compound (I1):

[0117]

[0118] Paclitaxel 10 (51.18 mg, 0.06 mmol) and Pd(OAc)2 (2.69 mg, 0.012 mmol) were suspended in 1.00-1.50 mL of HFIP (hexafluoroisopropanol), and then AgOAc (2.69 mg, 0.012 mmol), KF (10.46 mg, 0.18 mmol) and aryl iodide (0.06 mmol) were added in sequence. The pressure tube was sealed, and then the reaction was placed at a temperature of 100°C and stirred for 12 hours. After the reaction was completed, the pressure tube was cooled to room temperature, the reaction mixture was diluted with DCM, and filtered through short diatomaceous earth to collect the filtrate. The solvent was evaporated in vacuo and purified by PTLC (methanol: dichloromethane = 1:21; Rf = 0.3) to obtain compound Ⅰl (17.50 mg, yield 22%), and its nuclear magnetic resonance hydrogen spectrum can be found in Fig.23 , its carbon NMR spectrum can be found at Fig.24 .

[0119] 1H NMR(500MHz,DMSO-d6)δ8.96(dd,J=48.0,8.9Hz,1H),8.64(s,1H),8.06(t,J=8.8Hz,2H),7.97–7.93(m,1H),7.93–7.89(m,2H),7.86(dd,J=7.7,3.0Hz,2H),7.78(ddd,J=8.4,5.1,1.6Hz,1H),7.67–7.62(m,2H),7.61–7.58(m,1H),7.56(d,J=3.6Hz,1H),7.55–7.52(m,2H),7.51–7.49(m,3H),7.47(dt,J=8.0,2.5Hz,1H),7.42–7.38(m,2H),7.32(t,J=7.6Hz,2H),7.13(t,J=7.3Hz,1H),7.09(s,1H),6.27(s,1H),6.23–6.19(m,1H),5.88(t,J=9.1Hz,1H),5.60(s,2H),5.42–5.37(m,1H),5.26(d,J=4.6Hz,2H),5.00(dd,J=6.7,1.9Hz,1H),4.83–4.79(m,1H),4.71(s,1H),4.42(t,J=7.6Hz,1H),4.12–4.05(m,1H),3.98(d,J=8.2Hz,1H),3.93(t,J=7.5Hz,1H),2.36–2.31(m,2H),2.26(s,1H),2.11(d,J=5.9Hz,5H),2.08(d,J=2.6Hz,1H),1.84(t,J=12.2Hz,1H),1.78–1.74(m,3H),1.70(s,1H),1.57(s,1H),1.49(d,J=3.9Hz,3H),1.20(d,J=3.9Hz,2H),1.06(t,J=7.4Hz,4H),1.01(s,3H),0.90(s,1H),0.86(s,1H)。

[0120] 13C NMR (126MHz, DMSO) δ203.03,173.25,170.28,169.41,169.13,167.66,165.94,165.73,164.83,157.17,152.55,148.22,1 46.62,146.04,139.73,138.57,138.25,137.45,133.81,132.21,130.29,130.11,129.95,129.51,129.10,128.79,128.6 3,128.43,127.84,127.77,127.23,119.38,84.55,84.02,80.65,78.74,77.21,76.73,75.25,74.03,70.94,70.21,66.87 ,57.91,56.49,50.73,46.51,43.41,30.91,26.69,22.83,21.69,21.10,14.27,11.36,10.18,8.16.HR-MS(ESI):m / zcalcd for C74H69N3O19[M+Na]+1326.4417, found 1326.4407.

[0121] Example 13: Anti-tumor activity detection of compounds:

[0122] The human tumor cell lines MCF-7, A549 and SK-OV-3 and human embryonic kidney cells Herk 293T were suspended in DMEM cell culture fluid and inoculated in 4 T25 culture dishes respectively, and marked. The T25 was placed in a constant temperature cell culture incubator at 37°C and 5% CO2 (the setting conditions of the subsequent constant temperature incubator were all 37°C and 5% CO2). The growth state was continuously observed. After the cells adhered to the wall and covered the entire T25 culture dish, the four cells were washed with PBS buffer and digested with trypsin digestion solution, centrifuged and discarded the supernatant, and the cells were resuspended with DMEM culture fluid for cell inoculation. Take an appropriate amount of cell suspension and inoculate it into different 96-well plates at a density of 5000 cells / 100 μL culture fluid per well, and mark it. The 96-well plate was placed in a constant temperature cell culture incubator and cultured for 24 hours until it adhered to the wall. A total of 13 compounds, including 12 compounds Ⅰa, Ⅰb, Ⅰc, Ⅰd, Ⅰe, Ⅰf, Ⅰg, Ⅰh, Ⅰi, Ⅰj, Ⅰk, Ⅰl and the positive control drug paclitaxel, were prepared into a 10mM mother solution with dimethyl sulfoxide (DMSO) solution, and the mother solution was diluted with DMEM culture medium to twice the drug administration concentration. 9 concentration gradients (20μM, 10μM, 5μM, 2.5μM, 1.25μM, 0.625μM, 0.3125μM, 0.156μM, 0.078μM) were set, and there was another blank group to zero. Each concentration of each drug had three parallel groups. After the cells in the 96-well plate adhered to the wall, 100μL of drug dilution was added to the 96-well plate in sequence according to the concentration, and the blank group was added with an equal volume of DMEM culture medium. After the addition of drugs, the 96-well plate was placed in a constant temperature cell culture incubator for 48 hours. After the incubation, add 5mg / mL MTT staining solution to the 96-well plate, 10μL per well. Then put the 96-well plate back into the constant temperature incubator and incubate for 4h. Then take out the 96-well plate from the incubator, discard the supernatant, add 150μL of DMSO solution to each well to dissolve the blue-purple crystalline formazan deposited at the bottom of the well plate, shake well, and measure the absorbance at a wavelength of 490nm with an enzyme reader. Use GraphPad Prism 8.0.1 to process the data and calculate the IC50 value of the compound. The results are shown in Table 1:

[0123] Table 1: Antitumor activity testing of paclitaxel C(sp2)-H arylated derivatives.

[0124]

[0125] Example 14: Colocalization Cell Imaging of Compound Ij Since coumarin itself has fluorescence properties, the coupling compound Id of paclitaxel and coumarin also has blue fluorescence. The fluorescence performance of compound Ij is very good (excitation ex = 340nm, emission em = 450nm) detected by microplate reader. Compound Ij was added to the cell imaging culture dish cultured with MCF-7 at concentrations of 2.5μM, 5μM and 10μM, respectively. The paclitaxel-rhodamine probe (PTX-RB) reported before was used as a control. After incubation for 15 minutes, confocal imaging was performed. The results are shown in FIG. Fig.25 .

[0126] The results showed that the distribution of compound Ij in MCF-7 cells had localization ability. When the compound concentration was 2.5 μM, the Peterson correlation coefficient of the two compounds was 0.84, but when the probe concentration was increased to 10 μM, the Peterson correlation coefficient of the two compounds reached 0.94. 2 )-H bond arylation modification method successfully constructed a paclitaxel-coumarin fluorescent compound, which can be used for cell imaging and has a certain positioning ability. This proves that the C(sp 2 )-H bond arylation modification method has potential applications in cell biology.

Claims

1. A C(sp2)-H arylated derivative of paclitaxel, characterized in that: Its structure is shown in formula (Ij):

2. A method for preparing a C(sp2)-H arylated derivative of paclitaxel as claimed in claim 1, characterized in that: Taking paclitaxel represented by formula (II) as substrate, Dissolve in a solvent, add the aryl iodide shown in the following formula, A catalyst, an additive and an oxidant are added to react. After the reaction is completed, the resulting mixture is post-treated to obtain a paclitaxel-containing C(sp2)-H arylated derivative shown in formula (Ij).

3. The method for preparing a paclitaxel C(sp2)-H arylated derivative according to claim 2, characterized in that: The catalyst is palladium acetate; the oxidant is silver acetate; and the additive is potassium fluoride.

4. The method for preparing a paclitaxel C(sp2)-H arylated derivative according to claim 2, characterized in that: The molar ratio of paclitaxel represented by formula (II), aryl iodide represented by formula (III), catalyst, oxidant and additive is 1-1.2:1-1.2:1-2:1.2:

3.

5. The method for preparing a paclitaxel C(sp2)-H arylated derivative according to claim 2, characterized in that: The reaction is carried out at 70-110°C.

6. The method for preparing a paclitaxel C(sp2)-H arylated derivative according to claim 2, characterized in that: The concentration of the substrate in the solution is 0.05-0.1 mol / L.

7. The method for preparing a paclitaxel C(sp2)-H arylated derivative according to claim 2, characterized in that: The post-treatment is as follows: after the reaction mixture is cooled to room temperature, the reaction mixture is diluted with dichloromethane, filtered through short diatomaceous earth, the filtrate is collected, the solvent is evaporated in vacuo, and further purified by column chromatography or preparative thin layer chromatography (PTLC) to obtain the final paclitaxel-containing C(sp2)-H arylated derivative shown in (I).

8. Use of the C(sp2)-H arylated derivative of paclitaxel as claimed in claim 1 in the preparation of anti-tumor drugs.

9. Use of the C(sp2)-H arylated derivative of paclitaxel as claimed in claim 1 in the preparation of a fluorescent probe targeting tumor tubulin.

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