Tricyclic diterpene derivatives, preparation method thereof, and application thereof in the preparation of antitumor drugs

An anti-tumor drug and a technology for tricyclic diterpenes, which are applied in the fields of medicine and their preparation and application, can solve the problems of low content of diterpenoids, restrict in-depth research and clinical application, etc. mild effects

Active Publication Date: 2016-08-17
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the content of diterpenoids extracted from plants is often very small, which restricts their in-depth research and clinical application.

Method used

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  • Tricyclic diterpene derivatives, preparation method thereof, and application thereof in the preparation of antitumor drugs
  • Tricyclic diterpene derivatives, preparation method thereof, and application thereof in the preparation of antitumor drugs
  • Tricyclic diterpene derivatives, preparation method thereof, and application thereof in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the preparation of compound shown in formula (5)

[0040]

[0041] The preparation of tricyclic diterpene derivatives shown in formula (5), namely compound 5: Dissolve compound 1 (8g, 29.19mmol) in 50ml dichloromethane, slowly add Br 2 (1.5ml, 29.19mmol) of dichloromethane solution (50ml), after the dropwise addition, stir for 1h, TLC detects that the reaction of raw materials is complete, add water 50ml, extract the aqueous phase with dichloromethane (30ml×3), combine the organic phases, Wash with water (30ml×2), saturated NaHCO 3 Wash (30ml×2), wash with saturated brine (30ml×2), dry over anhydrous sodium sulfate, and concentrate to give compound 2 as a yellow oil, which is directly used in the next step.

[0042] The previous step crude product compound 2 (10.2g, 29mmol), TBSCl (6.5g, 43.5mmol), imidazole (3.95g, 58mmol) were placed in a single-necked bottle, DMF50ml was added, N 2 Replace and stir overnight at room temperature. TLC detects that t...

Embodiment 2

[0045] Embodiment 2: formula (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), ( Preparation of Tricyclic Diterpene Derivatives Shown in 17), (18), (19), (20), (21)

[0046]

[0047] The preparation of tricyclic diterpene derivatives shown in formula (6), namely compound 6: Compound 5 (100mg, 0.314mmol), EDC HCl (120.4mg, 0.628mmol), HOBt (84.8mg, 0.628mmol), DMAP ( 153.2mg, 1.256mmol) and aniline (88mg, 0.942mmol) were placed in a single-necked bottle, N 2 For replacement, 10ml of anhydrous dichloromethane was added, and stirred at room temperature overnight. TLC detects that the reaction of the raw materials is complete, add 10ml of water, adjust the pH of the system to 1 H NMR (400MHz, CDCl 3 )δ9.80(s,1H),7.96(s,1H),7.66(d,J=7.9Hz,2H),7.35(t,J=7.8Hz,2H),7.11(t,J=7.4Hz, 1H), 6.87(s, 1H), 4.01(s, 3H), 3.33(dd, J=11.1, 5.0Hz, 1H), 3.07–2.76(m, 2H), 2.30(dt, J=12.9, 3.1Hz ,1H),2.00–1.67(m,4H),1.67–1.58(m,1H),1.37–1.29(m,1H),1.23(s,3H),1.09(s,3H),0.92(s,3H )....

Embodiment 3

[0063] Embodiment 3: the preparation of tricyclic diterpene derivative shown in formula (27), (28)

[0064]

[0065] The preparation of tricyclic diterpene derivatives shown in formula (27), that is, compound 27: compound 13 (110 mg, 0.26 mmol), tert-butyldimethylsilyl chloride (201.4 mg, 1.33 mmol), imidazole (181.7 mg, 2.67 mmol) placed in a single-necked bottle, N 2 For replacement, inject 10ml of anhydrous DMF and stir overnight at room temperature. TLC detected that the reaction of raw materials was complete, added 10ml of water, extracted the aqueous phase with ethyl acetate (10ml×3), combined the organic phases, washed with water (10ml×2), washed with saturated brine (10ml×2), dried over anhydrous sodium sulfate, concentrated , silica gel column chromatography (PE:EA=10:1), concentrated to give compound 23 (99mg, 70.9%)

[0066] Compound 23 (168 mg, 0.319 mmol) obtained from the above reaction was placed in a single-necked bottle, N 2 For replacement, inject 10ml of...

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Abstract

The invention discloses a tricyclic diterpene derivative represented by the formula (I) and a preparation method thereof. The target product is prepared by carrying out amidation reaction, protective reaction, deprotection reaction and the like on a tricyclic diterpene primer. The invention further provides an application of the tricyclic diterpene derivative in preparation of an anti-tumour drug.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a tricyclic diterpene derivative, its preparation method, and its application in the preparation of antitumor drugs. Background technique [0002] Tumor is the abnormal proliferation of cells in the human body. Under the stimulation of various carcinogenic factors, local tissue cells in the biological body lose the normal regulation of cell proliferation at the genetic level, resulting in abnormal and excessive cell proliferation. Tumors are divided into benign tumors and malignant tumors according to the size and growth characteristics of the harm to the human body. Cancer is a general term for a large class of malignant tumors. It seriously threatens human health and is one of the leading causes of death in the world. About 1.4 million people die of cancer in my country every year. Although existing clinical drugs can alleviate ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/66C07C231/12C07C231/02A61P35/00A61P35/02
CPCY02P20/55
Inventor 仇文卫汪滢滢贺源易正芳刘明耀
Owner EAST CHINA NORMAL UNIV
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