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Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof

A compound and natural product technology, applied in the direction of antineoplastic drugs, organic chemistry, drug combination, etc., can solve the problems of poor water solubility and limited wide application

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

[0005] 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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  • Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof
  • Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof
  • Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of 7,10-diTroc-baccatin 2

[0037] Slowly add 20.5 mmol of trichloroethoxycarbonyl chloride (TrocCl) dropwise to 10-DAB (10 mmol) dissolved in pyridine at 63-95°C, stir magnetically, and monitor with TLC (petroleum ether-AcOEt) After the reaction was complete, the reaction solution was cooled to room temperature and pyridine was removed under reduced pressure, and the residue was 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...

Embodiment 2

[0038] Example 2 Synthesis of 10-Ac-baccatin 13

[0039] 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

[0040] Example 3 Synthesis of 7-Troc-10-Ac-baccatin 14

[0041] At 50-93°C, slowly add 9.8 mmol of trichloroethoxycarbonyl chloride (TrocCl) dropwise to compound 13 (9.3 mmol) dissolved in pyridine, stir magnetically, monitor the completion of the reaction by TLC, and cool the reaction solution to room temperature and remove pyridine, 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 12 with a yield of 84.2%. m.p.154.8-158.2°C. 1 H NMR (400MHz, 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 docetaxel side chain 2'-derived novel taxanes antitumor compound shown as the general structure formula (I) as well as a synthesis method and application thereof. In the formula, X is N or O, R is H or acetyl, and R' is H, nitryl, cyano, methoxyl or a halogen group. The synthesis method takes 10-deacetylbaccatin is used as a raw material; after 7-OH and 10-OH are protected, condensation with phenylisoserine (side chain) protecting 3'-NHBoc and 2'-OH in the presence of condensation agents DCC (Dicyclohexylcarbodiimide) and DMAP (Dimethylaminopyridine) is performed; esterification with substituted phenyl isoxazole carboxylic acid or substituted phenyl oxadiazole methyl carboxylic acid in the presence of the DCC and the DMAP is performed; finally, a protecting group is removed to obtain the compound. The compound disclosed by the invention has relatively high activity on tumor cells.

Description

technical field [0001] The invention relates to a novel taxane antitumor compound derived from the side chain 2'- of docetaxel and its synthesis method and application, belonging to the field of medicine and health. Background technique [0002] 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. In my country, the situation is not optimistic. According to the China Cancer Registration Annual Report released in 2013, the incidence of cancer in the whole country is very serious, and the morbidity and mortality are showing a continuous upward trend. 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 3 million. Therefore, there will be a great market demand for antineoplastic drugs on a global scal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D405/12A61P35/00
CPCY02P20/55C07D413/12C07D405/12
Inventor 张秀荣张生勇陈明金瑛梁承武昌盛李晓晔刘雪英陈卫平关韶宇
Owner JINLIN MEDICAL COLLEGE
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