L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof

A technology of ester trifluoroacetate and oridonin A, applied in the field of L-alanine-ester trifluoroacetate and its preparation, can solve the difficulty of intravenous administration, reduce activity, and fail to reach blood drug Concentration and other issues

Active Publication Date: 2014-09-03
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the oral bioavailability of oridonin is less than 5%, and the effective blood concentration cannot be reached; at the same time, oridonin is almost insoluble in water, so it is difficult to administer intravenously
Acylation at the 6-position and diacylation at the 6,14-position reduce its activity

Method used

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  • L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof
  • L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof
  • L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of N-Boc-L-alanine-(14-Oridonin A) Ester (III)

[0028] 150g (0.41mol) oridonin (II), 195g (1.04mol) BOC-L-Ala was suspended in 1.35kg dichloromethane, cooled to 0-5°C in an ice bath, and 213g (1.04mol) bicyclic Hexylcarbodiimide (DCC), stirred for 0.5h, removed the ice bath, stirred at room temperature for 5h, TLC confirmed the complete reaction of raw materials (dichloromethane:methanol=10:1, raw material R f =0.4, product R f =0.6). The reaction solution was cooled to 0°C and stood for 2h, filtered, and the filter cake was washed with dichloromethane (300g×3). The organic layers were combined and concentrated to obtain a white solid. Flash silica gel column chromatography (dichloromethane:methanol=100:1~60:1; v / v), collect product components, concentrate to dryness under reduced pressure to obtain about 140~165g of white solid powder. Add 600g of isopropyl ether to the above white powder, stir and wash for 2 hours, filter, wash the filter cake with iso...

Embodiment 2

[0031] Preparation of L-alanine-(14-oridonin A) ester trifluoroacetate (I)

[0032] 120g (0.224mol) of N-BOC-L-alanine-(14-oridonin A) ester (III) was dissolved in 600g of dichloromethane and cooled to 0°C. Slowly add 2.5kg of trifluoroacetic acid / dichloromethane (1:1; w / w) mixed solution dropwise at 0-5°C, and the addition is completed within 20 minutes. Stir at 0-5°C for 30 minutes, TLC confirmed that the reaction was complete (dichloromethane:methanol=10:1, raw material R f =0.6, product R f =0.3), the reaction solution was concentrated under reduced pressure to obtain light yellow to light red oil. After adding 7.2kg of isopropyl ether and stirring, a large amount of light yellow solid was precipitated. After stirring for 1 hour, it was filtered, and the filter cake was washed with isopropyl ether (145g×3). Dry in a vacuum oven to obtain 105-116 g of off-white or light yellow solid, with a yield of 85-94%. (HPLC>98%).

[0033]1 H-NMR (400MHz,MeOD):6.16(s,1H),6.10(s,1H...

Embodiment 3

[0036] According to the synthetic method of embodiment 1,2, the obtained L-alanine-(14-oridonin) ester trifluoroacetate, the acceleration of three batches of samples (25 ℃ ± 2 ℃, RH60% ± 10 %), long-term (2 ~ 8 ℃, RH60% ± 10%) stability investigation is shown in Table 1 and Table 2 below, the experimental data results show that the stability of the sample is good.

[0037] Table 1. Accelerated (25°C±2°C, RH60%±10%) test results

[0038]

[0039] Note: "--" means not detected.

[0040] Table 2. Long-term (2-8°C, RH60%±10%) test results

[0041]

[0042] Note: "--" means not detected.

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Abstract

The invention relates to L-alanine-(14-oridonin) ester trifluoroacetate as well as a preparation method and application thereof. The preparation method of the compound comprises the following steps of: by taking oridonin (II) as a starting material, generating 14-position esterification reaction with N-BOC-L-alanine in the presence of DCC to obtain N-BOC-L-alanine oridonin ester (III), removing a BOC protective group in trifluoroacetic acid, and salt-forming to obtain L-alanine-(14-oridonin) ester trifluoroacetate (I). The compound can be applied to clinic very well, and is used for treating esophagus cancer, gastric cancer, primary liver cancer, pancreatic cancer, cardia cancer, colorectal cancer, bladder cancer, breast cancer, acute myelogenous leukemia, and the like.

Description

technical field [0001] The present invention relates to a trifluoroacetic acid salt of a derivative of Rubescensin A and a preparation method thereof, specifically, the present invention relates to L-alanine-(14-Rabescensin A) ester trifluoroacetic acid Salt and method for its preparation. Background technique [0002] As early as the 1970s, the good anti-cancer activity of the Lamiaceae Lamiaceae plant, Rubescens genus, has attracted people’s attention. Rubescens contains monoterpenes, diterpenes, triterpenes and other terpenoids, as well as alkaloids, Steroids, flavonoids, volatile oils, amino acids, organic acids, monosaccharides and other ingredients, and have anti-tumor, anti-bacterial and anti-inflammatory, immune-enhancing, anti-oxidation, anti-mutation, antihypertensive and other pharmacological effects. Oridonin is a natural organic compound of kaurene diterpenoids extracted from Oridonin. The structure is as follows, accounting for more than 90% of the active ingr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/08A61K31/352A61P35/00A61P35/02
CPCY02P20/55C07D493/08
Inventor 孙飘扬武乖利邱振均陈永江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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