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19-carboxyl andrographolide derivative, preparation method and medicinal application thereof

A technology of andrographolide and its derivatives, which is applied in the fields of antineoplastic drugs, drug combinations, organic chemistry, etc., and can solve problems such as unstable physical and chemical properties of andrographolide, and destruction of the lactone ring structure

Inactive Publication Date: 2013-03-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the unstable physical and chemical properties of andrographolide, in the structural modification of its anti-tumor, the existing research work either has a small change, only acylation of 3, 14, 19-OH, or has a large change but destroys complete lactone ring structure

Method used

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  • 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof
  • 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof
  • 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] 3, Preparation of 19-isopropoxy-andrographolide:

[0052] Dissolve andrographolide (10.00g, 28.54mmol) in dry toluene / DMSO (200ml / 27ml), add 2,2-dimethoxypropane (14ml), p-toluenesulfonic acid (catalytic amount), 80°C Stir for about 1.5 hours until the reaction is complete, cool to room temperature, add triethylamine (7ml) to quench the catalyst, add toluene (150ml) to the reaction solution and wash with water (3×300ml), separate the organic layer, and dry over anhydrous sodium sulfate. Concentrate the dry organic phase, add diethyl ether (30ml), stir, filter and dry with suction to obtain white solid particles (10.36g, 26.53mmol, yield 93%). 1 H-NMR (300MHz, CDCl 3 , ppm) δ: 6.96 (1H, t, J=6.4Hz, H-12), 5.03 (1H, d, J=5.9Hz, H-14), 4.91 (1H, s, H-17a), 4.63 ( 1H, s, H-17b), 4.48-4.43 (1H, dd, J=10.4Hz, 6.1Hz, H-15a), 4.28-4.24 (1H, dd, J=1.9Hz, 10.4Hz, H-15b) , 3.97 (1H, d, J=5.8Hz, H-19a), 3.52-3.48 (1H, dd, J=3.4Hz, 8.4Hz, H-3), 3.2 (dd, 1H, H-19b), 2.64 -2.40(4H...

Embodiment 2

[0054] Preparation of 14-O-acetyl-andrographolide:

[0055] 3,19-isopropoxy-andrographolide (7.00g, 17.93mmol), Ac 2 O (60ml) was refluxed at 142°C for about 1.5 hours until the reaction was complete, cooled to room temperature, added a small amount of water and an appropriate amount of sodium bicarbonate powder and stirred until no bubbles overflowed, diluted the reaction solution with dichloromethane (100ml), and separated the organic layer And washed with saturated sodium bicarbonate solution (3X120ml) and saturated brine (3X120ml) successively. The organic phase is directly concentrated without drying, and then the concentrated crude product 3,19-isopropoxy-14-acetyl-andrographolide is dissolved in an aqueous solution of acetic acid (acetic acid: water=28ml: 12ml) at room temperature, and the reaction After completion, add sodium bicarbonate powder and stir until no bubbles overflow, dilute the reaction solution with dichloromethane (80ml), separate the organic layer and ...

Embodiment 3

[0057] Preparation of 14-O-acetyl-19-formyl-andrographolide:

[0058] 14-O-acetyl-andrographolide (5.00g, 12.74mmol) was dissolved in dichloromethane (130ml), and TEMPO (0.10g, 064mmol), potassium carbonate-carbonic acid with a pH of about 9 were added successively under an ice bath. Sodium hydrogen buffer solution (130ml), TBAI (0.24g, 0.65mmol) and NCS (2.40g, 17.97mmol), stirred vigorously for about 9 hours until the reaction was complete. After the reaction was complete, the organic layer was separated, the aqueous layer was extracted with dichloromethane (2×100ml), the organic layer was washed with saturated brine (2×300ml), and dried over anhydrous sodium sulfate. The dry organic phase was concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 2:1) to finally obtain a dry pale yellow foamy substance (4.52 g, 11.57 mmol, yield 91%). mp: 60-61°C. 1 H-NMR (300MHz, CDCl 3 , ppm) δ: 9.77 (1H, s, H-19), 7.01 (1H, t, J=6.8Hz,, H-12), 5.92 (1H, ...

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Abstract

The invention discloses a 19-carboxyl andrographolide derivative, a preparation method and medicinal application thereof, belonging to the field of medicinal chemistry. The 19-carboxyl andrographolide derivative has a structure general formula shown in 1, wherein R1 is substituted or unsubstituted C1-8 aliphatic acyls, and substituted or unsubstituted benzoyl; R2 is hydrogen, substituted or unsubstituted C1-8 aliphatic acyls, and substituted or unsubstituted benzoyl; and R3 is hydrogen, substituted or unsubstituted C1-8 aliphatic acyls, and substituted or unsubstituted phenyl. The invention also discloses a preparation method of the 19-carboxyl andrographolide derivative and application of the 19-carboxyl andrographolide derivative to preparation of anti-tumor drugs.

Description

technical field [0001] The invention relates to a synthesis method and a medical application of an andrographolide derivative, in particular to a synthesis method of a 19-carboxy andrographolide derivative and an application in preparing antitumor drugs, and belongs to the field of medicinal chemistry. Background technique [0002] The incidence of malignant tumors is increasing year by year, and has become a common disease that seriously endangers human health. Although there are many types of anti-tumor drugs currently on the market, they still cannot meet the clinical needs. Therefore, it is particularly urgent to develop new anti-tumor drugs with definite curative effect and less side effects. [0003] Andrographolide is a diterpene lactone compound extracted from Andrographis paniculata (Burm.f.) Nees, a plant of the Acanthaceae family. It is one of the main active ingredients of Andrographis paniculata (Burm.f.) Nees. Modern pharmacological studies have shown that and...

Claims

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Application Information

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IPC IPC(8): C07D307/60A61P35/00
Inventor 薛晓文陈东升宋雅萍
Owner CHINA PHARM UNIV
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