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Novel taxane anti-tumor compound as well as synthesis method and application thereof

A technology for compounds and products, applied in the field of medicine and health, can solve the problems of limited wide application and poor water solubility.

Inactive Publication Date: 2017-05-10
JINLIN MEDICAL COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although paclitaxel and docetaxel are very important antitumor drugs, their wide clinical application is limited due to their poor water solubility and the multidrug resistance (MDR) of tumor cells themselves developed during chemotherapy.

Method used

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  • Novel taxane anti-tumor compound as well as synthesis method and application thereof
  • Novel taxane anti-tumor compound as well as synthesis method and application thereof
  • Novel taxane anti-tumor compound as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Synthesis of 7,10-diTroc baccatin 1

[0038] At 63-95°C, slowly add 20.5 mmol of trichloroethoxycarbonyl chloride (TrocCl) dropwise into 10-DAB (10 mmol) 1 dissolved in pyridine, stir magnetically, and monitor the reaction by TLC. Cool to room temperature and remove pyridine under reduced pressure, and the residue is washed with AcOEt / H 2 After O was dissolved and diluted, the pH of the solution was adjusted to neutral with HCl. The solution was left to stand for stratification, the organic phase was separated, the aqueous phase was extracted with AcOEt, the organic phases were combined and successively washed with H 2 O, washed with saturated brine, anhydrous MgSO 4 After drying, the solvent was removed under reduced pressure to obtain a crude product, and 7,10-diTroc-baccatin 2 was obtained by column chromatography, the yield: 87.4%, m.p. 233.1-234.2°C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50(t, J = 7...

Embodiment 2

[0039] Example 2 Synthesis of 10-Ac-baccatin 2

[0040] Add 0.2 mol of acetic anhydride to 10 mmol of 10-DAB and ZnCl dissolved in 80 mL of anhydrous THF 2 20 mmol solution, reacted at room temperature, and added AcOEt / H 2 O with paste NaHCO 3 Adjust the pH of the solution to alkaline. Stand to separate the layers, separate the organic phase, extract the aqueous phase with AcOEt, combine the organic phases and successively use H 2 O, washed with saturated brine, anhydrous MgSO 4 After drying, the solvent was removed under reduced pressure to obtain a crude product. After recrystallization, the pure product of 10-Ac-baccatin 13 was obtained as a white solid, with a yield of 93%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 7.7 Hz, 2H), 7.63 (t, J =7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 6.34 (s, 1H), 5.64 (d, J = 6.9 Hz,1H), 5.00 (d, J = 9.1 Hz, 1H), 4.90 (t, J = 7.9 Hz, 1H), 4.48 (dd, J = 10.5,6.8 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 8.3 Hz, 1H),...

Embodiment 3

[0041] Example 3 Synthesis of 7-Troc-10-Ac Baccatin 3

[0042] Slowly add 9.8 mmol of trichloroethoxycarbonyl chloride (TrocCl) dropwise to 10-Ac baccatin 2 (9.3 mmol) dissolved in pyridine at 50-93°C, stir magnetically, and monitor the reaction by TLC The reaction solution was cooled to room temperature and pyridine was removed, and the residue was treated with AcOEt / H 2 After O was dissolved and diluted, the pH of the solution was adjusted to be slightly alkaline with HCl. The solution was left to stand for stratification, the organic phase was separated, the aqueous phase was extracted with AcOEt, the organic phases were combined and successively washed with H 2 O, washed with saturated brine, anhydrous MgSO 4 After drying, the solvent was removed to obtain a crude product, which was subjected to column chromatography to obtain 7-Troc-10-Ac baccatin 3 with a yield of 84.2%. m.p.154.8-158.2°C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.4...

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Abstract

The invention discloses a novel taxane anti-tumor compound shown in a structural formula (I). 10-DAB (10-deacetylbaccatin) is adopted as a raw material, and is condensed with phenylisoserine (side chain) with protected 3'-NH2 and 2'-OH in the presence of condensing agents DCC and DMAP after 7-OH and 10-OH are protected, the side chain and a protecting group on a baccatin ring are simultaneously removed in the presence of zinc powder, and coupling is performed with substituted phenylisoxazole in an alkaline medium to obtain a target product. The compound has relatively high anti-tumor activity. (The structural formula (I) is shown in the description.).

Description

technical field [0001] The invention relates to a novel taxane anti-tumor compound derived from the 3'-N side chain of paclitaxel, a synthesis method thereof and application of anti-tumor activity, and belongs to the field of medicine and health. [0002] technical background [0003] Cancer has become the second leading cause of death in humans after cardiovascular and cerebrovascular diseases. At the same time, with the deterioration of the environment and the aging of the population, this problem will become more prominent. According to the China Cancer Registration Annual Report released in 2013, the incidence of cancer nationwide is very serious, and both the incidence and mortality rates continue to rise. It is estimated that by 2020, the total number of cancer patients in China will reach 6.6 million and the total number of deaths will reach about 3 million. Therefore, there is a great market demand for antineoplastic drugs on a global scale. According to IMS statist...

Claims

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Application Information

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IPC IPC(8): C07D413/12A61P35/00
CPCY02P20/55C07D413/12
Inventor 金瑛张生勇陈明刘雪英李晓晔陈卫平关韶宇张秀荣梁承武昌盛
Owner JINLIN MEDICAL COLLEGE
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