CN111196839B - Thiostrepton derivative and preparation method thereof - Google Patents

Thiostrepton derivative and preparation method thereof Download PDF

Info

Publication number
CN111196839B
CN111196839B CN201911423872.8A CN201911423872A CN111196839B CN 111196839 B CN111196839 B CN 111196839B CN 201911423872 A CN201911423872 A CN 201911423872A CN 111196839 B CN111196839 B CN 111196839B
Authority
CN
China
Prior art keywords
mol
chloroform
reaction
thiostrepton
triethylamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201911423872.8A
Other languages
Chinese (zh)
Other versions
CN111196839A (en
Inventor
王守锋
范亚飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Jinan
Original Assignee
University of Jinan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Jinan filed Critical University of Jinan
Priority to CN201911423872.8A priority Critical patent/CN111196839B/en
Publication of CN111196839A publication Critical patent/CN111196839A/en
Application granted granted Critical
Publication of CN111196839B publication Critical patent/CN111196839B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a thiostrepton derivative and a preparation method thereof. The method is realized by the following steps: under the catalysis of triethylamine, thiostrepton reacts with aniline and derivatives thereof in chloroform, and the thiostrepton derivatives are obtained after HPLC semi-preparative separation. The method provided by the invention is carried out in a chloroform solvent under the catalysis of triethylamine, and has good substrate solubility and wide applicability; the reaction yield is high, and the controllability is strong. The method provided by the invention is green and environment-friendly, has few side reaction products, and is green and efficient.

Description

Thiostrepton derivative and preparation method thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an anti-gram-positive-bacterium antibiotic thiostrepton derivative and a preparation method thereof.
Background
The harm of infectious diseases is not eradicated along with the improvement of human science and technology, and 1500 million people still die directly from infection or diseases related to the infection every year; the pressure of global prevention and treatment is increased by the periodic outbreak of various new and old infectious epidemics; more seriously, the increasingly strong microbial resistance has made it difficult, if not impossible, to treat some diseases that were originally amenable to treatment, a phenomenon that is being anticipated and that has triggered a new public health crisis. Natural products, including antibiotics, are a major source of drug discovery and development. Many new drugs have been discovered and successfully developed from natural products in the past, such as Lovastatin, Reserpine, artemisinine, and the like. Natural products and derivatives thereof and synthetic drugs of the pharmacophore imitating the natural products account for higher proportion in the whole new drug family.
Thiostrepton (TSR) is firstly separated from Streptomyces azureus in soil in 1954, and researches show that TSR has broad-spectrum and good gram-positive bacteria inhibition activity. In vitro studies have shown that TSR binds to the gap between 23S rRNA and L11 protein in the large ribosomal 50S subunit, thereby blocking the binding of translation factors during bacterial protein synthesis. The site of action of TSR is distinct from all clinically used chemotherapeutic drugs, such as macrolide, lincosamide and aminoglycoside antibiotics. Although TSR is approved by FDA as a drug for the treatment of animal infectious diseases, TSR has poor water solubility and low bioavailability, and thus cannot reach a functional therapeutic concentration in vivo, which also becomes a main factor that restricts the application of TSR to the treatment of human diseases.
In order to solve this problem, it is necessary to find a method for obtaining a thiostrepton derivative having a high biological activity, which is easy to handle. Disclosure of Invention
Aiming at the problems that the existing thiostrepton derivatives are few in quantity, effective structure-activity relationship research and the research and development requirements of novel antibacterial drugs are difficult to carry out, the invention provides a novel thiostrepton derivative.
The invention also provides a preparation method of the thiostrepton derivative, and the method is simple and convenient to operate, wide in substrate application range, high in yield and strong in applicability.
The technical scheme adopted by the invention to achieve the aim is as follows: a thiostrepton derivative, having the formula:
Figure GDA0002440634140000021
wherein R is H, F, Cl, Br, I, CF3、CH3、O-CH3. The invention also provides a preparation method of the thiostrepton derivative, which comprises the following steps:
(1) adding thiostrepton, aniline or aniline derivatives and triethylamine into a chloroform solution for reaction, and collecting reaction liquid after the reaction is finished, wherein the chemical equation of the synthesized thiostrepton derivatives is as follows:
Figure GDA0002440634140000022
(2) and (3) carrying out column chromatography on the collected reaction liquid to obtain a crude extract of the thiostrepton derivative, and then preparing the pure thiostrepton derivative through semi-preparative HPLC, wherein the structural formula is as described above.
Further, the molar ratio of the thiostrepton to the aniline or the aniline derivative is 1:10-30, and the preferred molar ratio is 1: 20.
Further, the molar ratio of the thiostrepton to the triethylamine is 1:5-15, and the preferred molar ratio is 1: 10. Further, the molar concentration of the thiostrepton in the chloroform solution is 5 mmol/L.
Further, the reaction is carried out at the temperature of 15-30 ℃ for 12-36 hours, the preferred reaction temperature is 25 ℃, and the reaction time is 24 hours.
Further, the eluent in the column chromatography is methanol and dichloromethane according to a volume ratio of 1: 15. The invention has the beneficial effects that:
(1) the method provided by the invention is carried out in a chloroform solution under the catalysis of triethylamine, and has the advantages of good substrate solubility, wide applicability, high reaction yield and strong controllability.
(2) The method provided by the invention is green and environment-friendly, has few side reaction products, and is green and efficient. Detailed Description
The following examples further illustrate the technical solutions of the present invention, but should not be construed as limiting the scope of the present invention. The raw materials used in the present invention are all commercially available.
Example 1
20umol TSR, 400umol aniline, 200umol triethylamine were dissolved in 4mL chloroform and the reaction was carried out at 25 ℃ for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4a (31mg, yield 90%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.75(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.07(dd,J＝7.5,1.5Hz,2H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.93Hz,1H),6.67(dd,J＝7.5,2.2Hz,1H),6.58(dd,J＝7.5,1.5Hz,2H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H93N20O18S5(M+H+)m/z 1757.5575；found:1757.5577.
Example 2
20umol TSR, 400umol 2, 3-dimethylaniline and 200umol triethylamine were dissolved in 4mL of chloroform and the reaction was carried out at room temperature and 25 ℃ for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4b (28mg, yield 80%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.00(t,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.68(d,J＝7.2Hz,1H),6.45(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),,5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.28(s,3H),2.17(m,1H),2.12(s,3H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C80H97N20O18S5(M+H+)m/z 1785.5888；found:1785.5888.
Example 3
20. mu. mol of TSR, 400. mu. mol of 2-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction was completed, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4c (31mg, yield 84%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.30(d,J＝7.2Hz,1H),7.17(s,1H),7.14(t,J＝7.5Hz,1H),6.99(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.70(t,J＝7.5Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),,5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H92ClN20O18S5(M+H+)m/z 1791.5185；found:1791.5184.
Example 4
20. mu. mol of TSR, 400. mu. mol of 3-methyl-6-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product (4 g, 27mg, yield 74%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.27(d,J＝7.2Hz,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.68(s,1H),6.52(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),,5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.27(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94ClN20O18S5(M+H+)m/z 1805.5342；found:1805.5342.
Example 5
20. mu. mol of TSR, 400. mu. mol of 3-trifluoromethylaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4i (31mg, yield 84%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.07(t,J＝7.5Hz,1H),7.05(s,1H),6.99(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.47(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),,5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H92F3N20O18S5(M+H+)m/z 1825.5449；found:1825.5447。
Example 6
20. mu. mol of TSR, 400. mu. mol of 3-methylaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4n (30mg, yield 84%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.96(t,J＝7.5Hz,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.43(s,1H),6.40(d,J＝1.6Hz,1H),6.37(d,J＝7.2Hz,2H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),,5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.20(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H95N20O18S5(M+H+)m/z 1771.5731；found:1771.5733.
Example 7
20. mu. mol of TSR, 400. mu. mol of 2, 5-bistrifluoromethylaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4p (27mg, yield 71%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.31(d,J＝7.2Hz,1H),7.17(s,1H),6.99(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.86(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),,5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C80H91F6N20O18S5(M+H+)m/z 1893.5322；found:1893.5324.
Example 8
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-4-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and the objective product was obtained after semi-preparative purification after preliminary purification by column chromatography (30mg, yield 81%).
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.30(s,1H),7.17(s,1H),7.10(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.54(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FBrN20O18S5(M+H+)m/z 1853.4586；found:1853.4588.
Example 9
20umol TSR, 400umol 2, 4-difluoroaniline, and 200umol triethylamine were dissolved in 4mL of chloroform and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4w (28mg, yield 80%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.10(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.80(m,1H),6.77(d,J＝9.9Hz,1H),6.58(t,J＝8.0Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91F2N20O18S5(M+H+)m/z 1793.5386；found:1793.5386.
Example 10
20. mu. mol of TSR, 400. mu. mol of 2-methyl-3-fluoroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after preliminary purification by column chromatography, the objective product 4y (29mg, yield 84%) was obtained after semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.10(t,J＝7.5Hz,1H),7.00(dd,J＝8.0,7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.32(d,J＝7.2Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.25(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94FN20O18S5(M+H+)m/z 1789.5637；found:1789.5639.
Example 11
20. mu. mol of TSR, 400. mu. mol of 4-methyl-2-fluoroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4z (32mg, yield 86%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.86(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.74(d,J＝8.0Hz,1H),6.60(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.38(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94FN20O18S5(M+H+)m/z 1789.5637；found:1789.5637.
Example 12
20. mu. mol of TSR, 400. mu. mol of 3-fluoro-6-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction was completed, chloroform was removed by concentration, and the objective product 4aa (28mg, yield 79%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.30(d,J＝7.2Hz,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.73(d,J＝8.0Hz,1H),6.58(dd,J＝8.0,7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FClN20O18S5(M+H+)m/z 1809.5091；found:1809.5091.
Example 13
20umol TSR, 400umol 3-methyl-6-fluoroaniline, and 200umol triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ab (30mg, yield 84%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.07(dd,J＝8.0,7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.73(s,1H),6.58(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.28(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94FN20O18S5(M+H+)m/z 1789.5637；found:1789.5635.
Example 14
20. mu. mol of TSR, 400. mu. mol of 4-trifluoromethylaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ac (31mg, yield 85%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.37(d,J＝7.3Hz,2H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.48(d,J＝7.3Hz,2H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H92F3N20O18S5(M+H+)m/z 1825.5449；found:1825.5449.
Example 15
20. mu. mol of TSR, 400. mu. mol of 4-methyl-2-bromoaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4af (31mg, yield 84%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.22(s,1H),7.17(s,1H),7.05(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.52(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.38(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94BrN20O18S5(M+H+)m/z 1849.4836；found:1849.4836.
Example 16
20. mu. mol of TSR, 400. mu. mol of 2-methyl-4-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4ag (29mg, yield 81%) was obtained after semi-preparative purification after preliminary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.25(s,1H),7.22(d,J＝7.2Hz,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.51(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),2.14(s,3H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94BrN20O18S5(M+H+)m/z 1849.4836；found:1849.4836.
Example 17
20. mu. mol of TSR, 400. mu. mol of 3-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and the objective product was obtained after column chromatography preliminary purification and semi-preparative purification (28mg, yield 80%).
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.05(d,J＝7.2Hz,1H),6.99(t,J＝7.5Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.80(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.72(s,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H92BrN20O18S5(M+H+)m/z 1835.4680；found:1835.4680.
Example 18
20. mu. mol of TSR, 400. mu. mol of 2-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4aj (27mg, yield 75%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.62(d,J＝7.2Hz,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.20(t,J＝7.5Hz,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.84(m,1H),6.77(d,J＝9.9Hz,1H),6.56(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H92BrN20O18S5(M+H+)m/z 1835.4680；found:1835.4680.
Example 19
20. mu. mol of TSR, 400. mu. mol of 2-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product, 4ak (27mg, yield 70%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.09(d,J＝7.2Hz,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.22(t,J＝7.5Hz,1H),7.20(m,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.46(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H92IN20O18S5(M+H+)m/z 1883.4541；found:1883.4541.
Example 20
20. mu. mol of TSR, 400. mu. mol of 4-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4al (31mg, yield 81%) was obtained after semi-preparative purification after preliminary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.35(d,J＝7.2Hz,2H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.46(d,J＝7.2Hz,2H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H92IN20O18S5(M+H+)m/z 1883.4541；found:1883.4541.
Example 21
20umol TSR, 400umol 2,4, 5-trichloroaniline, 200umol triethylamine were dissolved in 4mL of chloroform and the reaction was carried out at room temperature for 24 hours. After the reaction was completed, chloroform was removed by concentration, and the objective product 4am (28mg, yield 75%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.80(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.80(s,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H90Cl3N20O18S5(M+H+)m/z 1859.4406；found:1859.4408.
Example 22
20. mu. mol of TSR, 400. mu. mol of 3-chloro-6-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4an (28mg, yield 75%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.37(d,J＝7.2Hz,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.80(s,1H),6.77(d,J＝9.9Hz,1H),6.72(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91ClBrN20O18S5(M+H+)m/z 1869.4290；found:1869.4290.
Example 23
20umol TSR, 400umol 4-chloro-2-bromoaniline, and 200umol triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ao (30mg, yield 78%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.65(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.14(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.50(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91ClBrN20O18S5(M+H+)m/z 1869.4290；found:1869.4290.
Example 24
20. mu. mol of TSR, 400. mu. mol of 3-fluoro-6-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ap (28mg, yield 75%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.50(d,J＝7.2Hz,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.68(d,J＝8.0Hz,1H),6.55(dd,J＝8.0,7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FBrN20O18S5(M+H+)m/z 1853.4586；found:1853.4588.
Example 25
20. mu. mol of TSR, 400. mu. mol of 3-methyl-2-fluoroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4aq (29mg, yield 80%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.90(t,J＝7.5Hz,1H),6.77(d,J＝9.9Hz,1H),6.60(d,J＝7.2Hz,1H),6.55(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.35(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94FN20O18S5(M+H+)m/z 1789.5637；found:1789.5637.
Example 26
20. mu. mol of TSR, 400. mu. mol of 4-fluoro-2-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ar (28mg, yield 76%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.70(d,J＝8.0Hz,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.90(dd,J＝8.0,7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.60(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FClN20O18S5(M+H+)m/z 1809.5091；found:1809.5093.
Example 27
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-3-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and the objective product 4as (30mg, yield 79%) was obtained after semi-preparative purification after preliminary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.93(t,J＝7.5Hz,1H),6.85(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.55(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FClN20O18S5(M+H+)m/z 1809.5091；found:1809.5091.
Example 28
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-5-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after preliminary purification by column chromatography, the objective product 4at (29mg, yield 78%) was obtained after semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.06(dd,J＝8.0,7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.87(s,1H),6.82(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FClN20O18S5(M+H+)m/z 1809.5091；found:1809.5091.
Example 29
20. mu. mol of TSR, 400. mu. mol of 4-methyl-2-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4au (29mg, yield 80%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.26(s,1H),7.17(s,1H),7.00(d,J＝7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.58(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.38(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94ClN20O18S5(M+H+)m/z 1805.5342；found:1805.5342.
Example 30
20. mu. mol of TSR, 400. mu. mol of 3-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4av (31mg, yield 84%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.27(d,J＝7.2Hz,1H),7.17(s,1H),7.05(t,J＝7.5Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.92(s,1H),6.82(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H92IN20O18S5(M+H+)m/z 1883.4541；found:1883.4541.
Example 31
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-5-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4aw (30mg, yield 81%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.00(dd,J＝8.0,7.2Hz,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.93(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.70(s,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FBrN20O18S5(M+H+)m/z 1853.4586；found:1853.4588.
Example 32
20. mu. mol of TSR, 400. mu. mol of 2, 5-dibromoaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ax (32mg, yield 84%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.37(d,J＝7.2Hz,1H),7.17(s,1H),6.97(d,J＝7.8,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.68(d,J＝7.2Hz,1H),6.62(s,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91Br2N20O18S5(M+H+)m/z 1913.3786；found:1913.3788.
Example 33
20. mu. mol of TSR, 400. mu. mol of 2,3, 4-trifluoroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction was completed, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4ay (28mg, yield 79%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.14(dd,J＝8.0,7.2Hz,1H),6.95(d,J＝6.6Hz,1H),6.90(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H90F3N20O18S5(M+H+)m/z 1811.5292；found:1811.5292.
Example 34
20umol TSR, 400umol 2, 3-difluoroaniline, and 200umol triethylamine were dissolved in 4mL of chloroform and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4ba (31mg, yield 83%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),7.00(t,J＝7.5Hz,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.60(dd,J＝8.0,7.2Hz,1H),6.45(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91F2N20O18S5(M+H+)m/z 1793.5386；found:1793.5388.
Example 35
20. mu. mol of TSR, 400. mu. mol of 2-methyl-4-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bb (30mg, yield 79%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.48(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.37(d,J＝7.2Hz,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.38(d,J＝7.2Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),2.15(s,3H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94IN20O18S5(M+H+)m/z 1897.4698；found:1897.4698.
Example 36
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-4-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bc (27mg, yield 73%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.27(d,J＝8.0Hz,1H),7.22(d,J＝7.2Hz,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.45(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FIN20O18S5(M+H+)m/z 1901.4447；found:1901.4447.
Example 37
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-4-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after preliminary purification by column chromatography, the objective product 4bd (29mg, yield 79%) was obtained after semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.30(d,J＝8.0Hz,1H),7.17(s,1H),7.10(d,J＝7.2Hz,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.58(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FBrN20O18S5(M+H+)m/z 1853.4586；found:1853.4588.
Example 38
20. mu. mol of TSR, 400. mu. mol of 2-methyl-5-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after preliminary purification by column chromatography, the objective product 4be (27mg, yield 77%) was obtained after semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.20(d,J＝7.2Hz,1H),7.17(s,1H),6.98(d,J＝7.2Hz,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.68(s,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),2.05(s,3H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94BrN20O18S5(M+H+)m/z 1849.4836；found:1849.4838.
Example 39
20. mu. mol of TSR, 400. mu. mol of 2-chloro-4-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bf (30mg, yield 78%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.58(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.32(d,J＝7.2Hz,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.36(d,J＝7.2Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91ClIN20O18S5(M+H+)m/z 1917.4151；found:1917.4151.
Example 40
20. mu. mol of TSR, 400. mu. mol of 3-methyl-6-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bg (30mg, yield 81%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.39(d,J＝7.2Hz,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.63(s,1H),6.50(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.30(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94BrN20O18S5(M+H+)m/z 1849.4836；found:1849.4838.
Example 41
20. mu. mol of TSR, 400. mu. mol of 2-methyl-3-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bh (28mg, yield 79%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.92(d,J＝7.2Hz,1H),6.89(t,J＝7.5Hz,1H),6.77(d,J＝9.9Hz,1H),6.50(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.28(s,3H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94BrN20O18S5(M+H+)m/z 1849.4836；found:1849.4836.
Example 42
20. mu. mol of TSR, 400. mu. mol of 2-fluoro-4-chloroaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and the objective product 4bi (28mg, yield 79%) was obtained after semi-preparative purification after primary purification by column chromatography.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.68(d,J＝8.0Hz,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.99(d,J＝7.2Hz,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.59(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FClN20O18S5(M+H+)m/z 1809.5091；found:1809.5091.
Example 43
20. mu. mol of TSR, 400. mu. mol of 4-fluoro-2-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bj (30mg, yield 79%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.27(d,J＝8.0Hz,1H),7.17(s,1H),7.00(dd,J＝8.0,7.2Hz,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.45(d,J＝7.2Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91FIN20O18S5(M+H+)m/z 1901.4447；found:1901.4449.
Example 44
20. mu. mol of TSR, 400. mu. mol of 4-bromo-2-iodoaniline and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bk (30mg, yield 78%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.75(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.39(d,J＝7.2Hz,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.37(d,J＝7.2Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91BrIN20O18S5(M+H+)m/z 1961.3646；found:1961.3648.
Example 45
20. mu. mol of TSR, 400. mu. mol of 4-chloro-2-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after preliminary purification by column chromatography, the objective product 4bl (28mg, yield 75%) was obtained after semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.55(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.20(d,J＝7.2Hz,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.38(d,J＝7.2Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H91ClIN20O18S5(M+H+)m/z 1917.4151；found:1917.4151.
Example 46
20. mu. mol of TSR, 400. mu. mol of 2-methyl-5-iodoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product, 4bm (28mg, yield 75%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.90(d,J＝7.2Hz,1H),6.86(s,1H),6.83(d,J＝7.2Hz,1H),6.77(d,J＝9.9Hz,1H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),2.02(s,3H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C79H94IN20O18S5(M+H+)m/z 1897.4698；found:1897.4696.
Example 47
20umol TSR, 400umol 3,4, 5-trifluoroaniline, and 200umol triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bn (29mg, yield 80%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.55(dd,J＝8.0,5.0Hz,2H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H90F3N20O18S5(M+H+)m/z 1811.5292；found:1811.5292.
Example 48
20. mu. mol of TSR, 400. mu. mol of 3, 5-difluoro-4-bromoaniline, and 200. mu. mol of triethylamine were dissolved in 4mL of chloroform and the mixture was allowed to stand at room temperature for 24 hours. After completion of the reaction, chloroform was removed by concentration, and after a preliminary purification by column chromatography, the objective product 4bo (32mg, yield 85%) was obtained after a semi-preparative purification.
1H NMR(600MHz,CDCl3:CD3OD(4:1)):δ9.85(s,1H),9.75(s,1H),8.98(s,1H),8.16(s,1H),8.15(s,1H),8.03(s,1H),7.87(s,1H),7.45(d,J＝13.1,1H),7.43(d,J＝13.1,1H),7.41(s,1H),7.17(s,1H),6.95(d,J＝6.6Hz,1H),6.77(d,J＝9.9Hz,1H),6.46(d,J＝8.0Hz,2H),6.40(d,J＝1.6Hz,1H),6.26(dd,J＝5.6,9.4Hz,1H),6.22(m,1H),6.09(q,J＝6.5Hz,1H),5.64(s,1H),5.61(d,J＝9.8Hz,1H),5.54(d,J＝1.7Hz,1H),5.47(d,J＝2.3Hz,1H),5.20(s,1H),5.19(s,1H),5.17(s,1H),4.86(dd,J＝9.7,11.8Hz,1H),4.60(m,1H),4.49(m,1H),4.29(m,1H),3.95(m,1H),3.70(m,1H),3.68(dq,J＝5.8,6.3Hz,1H),3.53(s,1H),3.52(dd,J＝2.3,5.5Hz,1H),3.44(m,1H),2.84(s,1H),2.17(m,1H),1.59(d,J＝6.4Hz,3H),1.49(d,J＝6.8Hz,3H),1.40(m,1H),1.30(d,J＝6.4Hz,3H),1.25(d,J＝6.6Hz,3H),1.17(d,J＝6.4Hz,3H),1.05(d,J＝9.0Hz,3H),1.02(s,3H),0.98(m,2H),0.87(d,J＝6.9Hz,3H),0.76(t,J＝6.4Hz,1H),0.69(d,J＝5.2Hz,3H).HRMS(ESI)calculated for C78H90F2BrN20O18S5(M+H+)m/z 1871.4491；found:1871.4491.
Comparative example 1
TSR (0.02mmol, 32mg), triethylamine (0.02mmol, 2.0mg), aniline (0.4mmol, 36ul) were added to 4mL of chloroform solution and reacted at 25 ℃ for 24 hours, the reaction solution was collected and subjected to column chromatography to give a crude extract, and semi-preparative HPLC to give 10.5mg of a pale yellow solid product with a yield of 31%.
Comparative example 2
TSR (0.02mmol, 32mg), triethylamine (0.4mmol, 40.4mg), aniline (0.4mmol, 36uL) were added to 4mL of chloroform solution and reacted at 25 ℃ for 24 hours, the reaction solution was collected, column chromatography was performed to obtain a crude extract, semi-preparative HPLC gave 14.2mg of a pale yellow solid product with a yield of 40%.
Comparative example 3
TSR (0.02mmol, 32mg), triethylamine (0.2mmol, 20.2mg), aniline (0.06mmol, 5.4uL) were added to 4mL of chloroform solution and reacted at 25 ℃ for 24 hours, the reaction solution was collected, column chromatography was performed to obtain a crude extract, semi-preparative HPLC gave 12.3mg of a pale yellow solid product, with a yield of 35%.
Comparative example 4
TSR (0.02mmol, 32mg), triethylamine (0.2mmol, 20.2mg), aniline (0.8mmol, 72uL) were added to 4mL of chloroform solution and reacted at 25 ℃ for 24 hours, the reaction solution was collected, column chromatography was performed to obtain a crude extract, semi-preparative HPLC gave 18.2mg of a pale yellow solid product with a yield of 52%.
Comparative example 5
TSR (0.02mmol, 32mg), triethylamine (0.2mmol, 20.2mg), aniline (0.4mmol, 36uL) were added to 4mL of chloroform solution and reacted at 25 ℃ for 6 hours, the reaction solution was collected, column chromatography was performed to obtain a crude extract, semi-preparative HPLC gave 11.9mg of a pale yellow solid product, with a yield of 34%.
Comparative example 6
TSR (0.02mmol, 32mg), triethylamine (0.2mmol, 20.2mg), aniline (0.4mmol, 36uL) were added to 4mL of chloroform solution and reacted at 25 ℃ for 48h, the reaction solution was collected and subjected to column chromatography to give a crude extract, and semi-preparative HPLC to give 15.9mg of a pale yellow solid product with a yield of 45%.
Comparative example 7
TSR (0.02mmol, 32mg), triethylamine (0.2mmol, 20.2mg), aniline (0.2mmol, 36uL) were added to 4mL of chloroform solution and reacted at 0 ℃ for 24 hours, the reaction solution was collected and subjected to column chromatography to give a crude extract, and semi-preparative HPLC to give 3.5mg of a pale yellow solid product with a yield of 9%.
Comparative example 8
TSR (0.02mmol, 32mg), triethylamine (0.2mmol, 20.2mg), aniline (0.2mmol, 36uL) were added to 4mL of chloroform solution and reacted at 50 ℃ for 24 hours, the reaction solution was collected and subjected to column chromatography to give a crude extract, and semi-preparative HPLC to give 5.3mg of a pale yellow solid product with a yield of 15%.
Effect examples drug sensitive Activity test method and results
TSR and its analogues were dissolved in DMSO to make 1mg/mL stock, and the antibiotic stock was diluted by broth dilution gradient to 50. mu.l of Mueller-Hinton medium previously placed in 96-well plates to obtain a final antibiotic concentration in the range of 0.5-0. mu.g/mL. About 50. mu.l of test bacterial suspension (107-. The method is used for carrying out parallel experiments for 3 times, the lowest drug concentration capable of inhibiting the test bacteria from obviously increasing is observed, and specific results are shown in table 1.
TABLE 1
Figure GDA0002440634140000261
Figure GDA0002440634140000271
Figure GDA0002440634140000281
When the aniline derivative is 2-methylaniline, 2, 4-dimethylaniline, 2-methyl-4-chloroaniline, 4-bromoaniline, 4-chloroaniline, 3, 5-bistrifluoromethylaniline, 2-fluoroaniline, 2-methyl-5-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2, 5-dichloroaniline, 2,4, 5-trifluoroaniline, 4-methylaniline or 2, 5-difluoroaniline, the thiostrepton derivative prepared by using the other compounds prepared by the preparation method provided by the invention also has an antibacterial effect, and the effect is better than that of TSR (TSR), and is relatively poorer than that of the derivative prepared by using the embodiment of the invention, and the specific results are shown in Table 2.
Figure GDA0002440634140000282
Figure GDA0002440634140000291

Claims (7)

1. A thiostrepton derivative, characterized in that the structural formula of the derivative is as follows:
Figure 900723DEST_PATH_IMAGE001
wherein R = H, F, Cl, Br, I, CF3、CH3 、O-CH3。
2. A process for the preparation of a thiostrepton derivative according to claim 1, characterized by comprising the following steps:
(1) adding thiostrepton, aniline or aniline derivatives and triethylamine into a chloroform solution for reaction, and collecting reaction liquid after the reaction is finished, wherein the chemical equation of the synthesized thiostrepton derivatives is as follows:
Figure 21125DEST_PATH_IMAGE002
；
(2) and (2) carrying out column chromatography on the collected reaction liquid to obtain a crude extract of the thiostrepton derivative, and then preparing the pure thiostrepton derivative by semi-preparative HPLC, wherein the structural formula of the thiostrepton derivative is as follows:
Figure 27562DEST_PATH_IMAGE003
wherein R = H, F, Cl, Br, I, CF3、CH3 、O-CH3。
3. The process according to claim 2, wherein the molar ratio of thiostrepton to aniline or aniline derivative is 1: 10-30.
4. The method according to claim 2, wherein the molar ratio of thiostrepton to triethylamine is 1: 5-15.
5. The method according to claim 2, wherein the molar concentration of thiostrepton in chloroform solution is 5 mmol/L.
6. The method according to any one of claims 2 to 5, wherein the reaction is carried out at a temperature of 15 ℃ to 30 ℃ for 12 to 36 hours.
7. The preparation method according to claim 2, wherein the eluent for the column chromatography is methanol and dichloromethane in a volume ratio of 1: 15, the components are mixed.
CN201911423872.8A 2019-12-31 2019-12-31 Thiostrepton derivative and preparation method thereof Active CN111196839B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911423872.8A CN111196839B (en) 2019-12-31 2019-12-31 Thiostrepton derivative and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911423872.8A CN111196839B (en) 2019-12-31 2019-12-31 Thiostrepton derivative and preparation method thereof

Publications (2)

Publication Number Publication Date
CN111196839A CN111196839A (en) 2020-05-26
CN111196839B true CN111196839B (en) 2022-06-10

Family

ID=70744511

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911423872.8A Active CN111196839B (en) 2019-12-31 2019-12-31 Thiostrepton derivative and preparation method thereof

Country Status (1)

Country Link
CN (1) CN111196839B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603871A (en) * 2011-01-20 2012-07-25 中国科学院上海有机化学研究所 Novel thiostrepton analog, as well as preparation method and application thereof
CN103102396A (en) * 2011-11-14 2013-05-15 中国科学院上海有机化学研究所 Novel thiostrepton analog, amd preparation method and application thereof
CN105085613A (en) * 2014-05-20 2015-11-25 中国科学院上海有机化学研究所 Novel thiostrepton analogue, and preparation method and application thereof
CN105777870A (en) * 2016-01-29 2016-07-20 中国科学院上海有机化学研究所 Novel thiostrepton analogue and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603871A (en) * 2011-01-20 2012-07-25 中国科学院上海有机化学研究所 Novel thiostrepton analog, as well as preparation method and application thereof
CN103102396A (en) * 2011-11-14 2013-05-15 中国科学院上海有机化学研究所 Novel thiostrepton analog, amd preparation method and application thereof
CN105085613A (en) * 2014-05-20 2015-11-25 中国科学院上海有机化学研究所 Novel thiostrepton analogue, and preparation method and application thereof
CN105777870A (en) * 2016-01-29 2016-07-20 中国科学院上海有机化学研究所 Novel thiostrepton analogue and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
硫肽类抗生素类似物合成进展;王守锋等;《有机化学》;20171231;第37卷(第7期);1653-1666 *

Also Published As

Publication number Publication date
CN111196839A (en) 2020-05-26

Similar Documents

Publication Publication Date Title
WO2008038965A1 (en) 7alpha-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for anticancer or antibiotics containing the same as an active ingredient
MX2014015249A (en) N-substituted second generation derivatives of antifungal antibiotic amphotericin b and methods of their preparation and application.
WO2012150606A2 (en) A process for preparing stable polymophic form of erlotinib hydrochloride
CN101360712A (en) New pleuromutilin derivative and its use
CN110551072A (en) quinoxaline-N 1, N 4 -dioxide derivative with DNA topoisomerase activity inhibition function, preparation method and application
CN112111410B (en) Preparation method of dibenzooxepinone compound
CN111196839B (en) Thiostrepton derivative and preparation method thereof
CN112110897B (en) Preparation method of deuterated crizotinib and derivative thereof
US10633337B2 (en) Crystal forms of a 9-aminomethyl substituted tetracycline compound and a preparation method thereof
CN111269247B (en) Preparation method of buprofezin drug molecule with escherichia coli inhibition effect
CN107151264B (en) Novel glycopeptide antibiotic derivative, pharmaceutical composition, preparation method and application thereof
CN110172058B (en) 7-azaspiro [5.6] dodecane-10-one compound and preparation method and application thereof
CN114539161A (en) Olaparib-urea eutectic crystal and preparation method thereof
CN111205285B (en) Purification method and crystal form of berberine or berberine salt
WO2022017317A1 (en) Method for large-scale synthesis of tetrodotoxin
CN107536835B (en) Application of 1, 3-diamino-7H-pyrrole [3,2-f ] quinazoline derivative as antibacterial drug and drug
CN110804058B (en) Novel ibrutinib crystal form and preparation method thereof
CN110964084B (en) Nosiheptide derivative and preparation method thereof
CN107602454B (en) Sulfonamide compound and preparation method and application thereof
CN109942543A (en) A kind of synthetic method of moxifloxacin hydrochloride light degradation impurity
CN110016013A (en) A kind of bis- target spot inhibitor of novel c-Met/HDAC and its synthetic method and application
CN111662351B (en) New octreolone type sapogenin derivative and application thereof in preparation of drug-resistant bacteria resistant drugs
CN106336363A (en) Safinamide mesylate crystal form C and preparation method thereof
CN111094313A (en) Crystalline form of idarubicin hydrochloride monohydrate
WO2013163917A1 (en) Compound jk12a and preparation thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant