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Oleanolic acid derivative, and preparation method and purpose thereof

A technology for oleanolic acid derivatives, applied in the field of preparation of oleanolic acid derivatives or pharmaceutically acceptable salts thereof, can solve the problems of low reactivity, high price, inflammability and explosion, and achieve The effect of high reaction yield, low production cost and mild reaction conditions

Inactive Publication Date: 2011-05-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above CDDO synthesis route mainly has the following disadvantages: ①Since the C28 carboxyl group in the oleanolic acid molecule is in the large steric hindrance shielding area of ​​the mother nucleus, the reactivity is low, so in step a, methyl iodide or diazomethane needs to be used to proceed smoothly Methylation reaction
However, these reagents have the disadvantages of being expensive, flammable, highly toxic, and difficult to preserve; ② step k involves the hydrolysis of the C28 carboxylate methyl ester of CDDO-Me, which cannot be carried out smoothly under conventional acid or alkaline conditions. To carry out, it needs to use expensive anhydrous lithium iodide as a reagent, and reflux in anhydrous DMF for a long time to complete
At the same time, the post-treatment of this reaction is cumbersome, requiring multi-step operations such as column chromatography and recrystallization.

Method used

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  • Oleanolic acid derivative, and preparation method and purpose thereof
  • Oleanolic acid derivative, and preparation method and purpose thereof
  • Oleanolic acid derivative, and preparation method and purpose thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Preparation of Benzyl 3β-Hydroxyoleanane-12-ene-28-carboxylate (II)

[0056] Oleanolic acid (100g, 220mmol) and K 2 CO 3 (61g, 440mmol) was placed in DMF (800mL), and benzyl chloride (33mL, 290mmol) was added dropwise within 20 minutes at 50-55°C. After dropping, the reaction was continued for 3-4 hours, cooled to room temperature, filtered, and the filter cake was Washed with DMF (50mL×3), the filtrate was poured into ice water (3000mL), a large amount of white solids were precipitated, left to stand until the solid particles became larger, filtered with suction, the solids were collected, fully washed with water, and dried to obtain a white solid II (114g , 95.5%). Compound II is a known compound with a CAS number of 303114-51-4.

Embodiment 2

[0058] Preparation of Benzyl 3β-Acetoxyoleanane-12-ene-28-carboxylate (III)

[0059] Compound II (5.46g, 10mmol) was dissolved in 20mL of pyridine, and acetic anhydride (10.2g, 100mmol) was slowly added dropwise at 0-5°C. After the addition was completed, DMAP (0.12g, 1mmol) was added, and a solid precipitated out. Continue to react for 1 to 2 hours, add an appropriate amount of dichloromethane (50mL) to dissolve, wash the solution with 5% HCl solution, saturated sodium bicarbonate solution, and saturated brine for 3 times, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure A white solid III (5.4 g, 91.3%) was obtained. Compound III is a known compound with a CAS number of 357953-27-6.

Embodiment 3

[0061] Preparation of Benzyl 3β-Acetoxy-12-oxooleanane-28-carboxylate (IV)

[0062] Compound III (5.88g, 10mmol) was dissolved in an appropriate amount of dichloromethane (50mL), added formic acid (10mL), H 2 o 2 (1.36g, 40mmol), reacted at room temperature for 24 hours, TLC monitored the reaction process, after the disappearance of the raw material point, the reaction solution was washed to near neutrality with saturated sodium bicarbonate solution, washed 3 times with saturated saline, dried over anhydrous sodium sulfate, After removing the solvent under reduced pressure, a light yellow solid was obtained, AcOH-H 2 O was recrystallized to give IV as a white solid (4.7 g, 78%). Compound IV is a known compound with CAS No. 357953-28-7.

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Abstract

The invention relates to the field of medicine, in particular to an oleanolic acid derivative shown as a formula I, and pharmaceutically acceptable salts, a preparation method and purpose thereof. The invention also discloses application of the compound shown by the formula I to the preparation of anti-tumor medicine of 2-cyano-3, 12-dioxo oleanane-1, 9(11)-diene-28-carboxylic acid (XI, CDDO), 2-cyano-3, 12-dioxo oleanane-1, 9(11)-diene-28-carboxylic imidazole (XIII, CDDO-Im) and 2-cyano-3, 12-dioxo oleanane-1, 9(11)-diene-28-carboxyl methylamine (XIV, CDDO-MA).

Description

technical field [0001] The present invention relates to the field of medicine, in particular to an oleanolic acid derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, and a preparation method thereof. The present invention still further relates to the compound shown in formula (I) in preparing antitumor drug 2-cyano group-3,12-dioxooleanane-1,9(11)-diene-28-carboxylic acid ( CDDO), 2-cyano-3,12-dioxooleanane-1,9(11)-diene-28-carboxyimidazole (CDDO-Im) and 2-cyano-3,12- Application in dioxooleanane-1,9(11)-diene-28-carboxamide (CDDO-MA). Background technique [0002] Oleanane-type (oleanane) pentacyclic triterpenoids represented by oleanolic acid (OA) are ubiquitous in nature and have a wide range of biological activities (Neoplasma, 2004, 51, 327-333), The optimization and derivation based on the structure of these natural compounds is one of the hotspots in the research of natural medicinal chemistry. [0003] [0004] 2-cyano-3,12-diox...

Claims

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Application Information

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IPC IPC(8): C07J63/00
Inventor 张奕华丁晔赖宜生张士薄黄张建彭司勋
Owner CHINA PHARM UNIV
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