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3-position modified derivative of 23-hydroxybetulinic acid, preparation method and application

A derivative, betulinic acid technology, applied in the field of 23-hydroxybetulinic acid 3-modified derivatives, preparation field, can solve rare problems

Active Publication Date: 2022-05-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, studies on the C3 locus are quite rare

Method used

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  • 3-position modified derivative of 23-hydroxybetulinic acid, preparation method and application
  • 3-position modified derivative of 23-hydroxybetulinic acid, preparation method and application
  • 3-position modified derivative of 23-hydroxybetulinic acid, preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] 3-Pyridylamide-23-acetyl-lupin-20(29)-ene-28-acid benzyl ester

[0049] 23-HBA (10.0 g, 21.0 mmol) was dissolved in DMF (120 mL), potassium carbonate (10.0 g, 72 mmol) and benzyl bromide (3 mL, 25.0 mmol) were gradually added to it, and 2 h was added after the reaction at room temperature for 2 h. twice the volume of water (240 mL), the product was precipitated, and the crude product was obtained by suction filtration (which can be directly added to the next step). 23-HBA derivative 1.

[0050] Compound 1 (1.00 g, 2.05 mmol) was dissolved in dichloromethane (40 mL), DMAP (0.052 g, 0.41 mmol) was added, acetic anhydride (211.7 μL, 2.26 mmol) was added dropwise under stirring, and the reaction was monitored at room temperature until The raw materials disappeared, the reaction solution was concentrated, extracted with ethyl acetate (50 mL×3), the organic layers were combined, washed three times with water, washed with saturated sodium chloride, dried over anhy...

Embodiment 2

[0054]

[0055] 3-Pyrazinamide-23-acetyl-lupin-20(29)-ene-28-acid benzyl ester

[0056] The synthesis method refers to the synthesis of Example 1, 48.9%. 1 H NMR (500MHz, Chloroform-d) δ 9.34 (d, J=3.8Hz, 1H), 8.74 (q, J=2.6Hz, 2H), 7.37-7.29 (m, 5H), 5.16-5.01 (m, 2H), 4.72 (d, J=2.4Hz, 1H), 4.60 (s, 1H), 4.25-4.11 (m, 2H), 3.97 (dd, J=16.3, 11.5Hz, 1H), 3.01 (td, J =10.8, 4.7Hz, 1H), 2.30-2.12(m, 2H), 2.08-1.99(m, 1H), 1.95(d, J=4.2Hz, 3H), 1.93-1.81(m, 3H), 1.76- 1.68(m, 3H), 1.64-1.53(m, 2H), 1.43(d, J=8.0Hz, 2H), 1.42-1.39(m, 2H), 1.38(d, J=6.4Hz, 2H), 1.35 -1.32 (m, 2H), 1.29 (d, J=4.9Hz, 2H), 1.27-1.24 (m, 2H), 1.04 (ddd, J=17.4, 8.0, 4.4Hz, 3H), 0.96 (d, J =17.7Hz, 2H), 0.92(d, J=4.8Hz, 1H), 0.89(d, J=2.8Hz, 3H), 0.86(s, 3H), 0.83(s, 1H), 0.77(s, 3H) ). 13 C NMR (125MHz, Chloroform-d) δ175.8, 169.6, 163.7, 150.5, 147.3, 146.2, 144.7, 143.9, 136.5, 128.5, 128.2, 128.0, 109.7, 67.9, 65.7, 56.5, 51.0, 50.9, 49.4, 49 ESI-MS m / z: 710.5[M+H] + ;HR-MS(ESI)m / z: cal...

Embodiment 3

[0058]

[0059] 3-Cyclohexaneamide-23-acetyl-lupin-20(29)-ene-28-acid benzyl ester

[0060] The synthesis method refers to the synthesis of Example 1, 45.7%. 1 H NMR (300MHz, Chloroform-d) δ 7.37-7.32 (m, 5H), 5.17-5.08 (m, 3H), 4.72 (s, 1H), 4.60 (s, 1H), 4.09-4.01 (m, 2H) ), 3.90(d, J=11.4Hz, 1H), 3.47(d, J=11.5Hz, 1H), 3.05-2.99(m, 1H), 2.40-2.26(m, 2H), 2.19(t, J= 10.6Hz, 1H), 1.95(s, 3H), 1.68(s, 3H), 0.93(s, 3H), 0.82(s, 3H), 0.75(s, 3H), 0.70(s, 3H); MS m / z: 714.5[M+H] + ;HR-MS(ESI)m / z: calculated for C 46 H 68 NO 5 [M+H] + : 714.5092, found: 714.5089.

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Abstract

The invention discloses a 3-position modified derivative of 23-hydroxy betulinic acid, a preparation method and an application. The present invention is based on the structural transformation of natural products to search for new drug molecules, and introduces aliphatic side chains of different sizes, benzene rings substituted by different groups at different positions, and nitrogen-containing heterocyclic substituents through the derivatization of the C3 hydroxyl group. A new type of anti-tumor compound with better activity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a 3-position modified derivative of 23-hydroxybetulinic acid, a preparation method and an application. Background technique [0002] The traditional Chinese medicine Pulsatilla chinensis (Bunge) Regel is a medicinal plant, and its roots are widely used in the adjuvant treatment of intestinal amebiasis, malaria, vaginal trichomoniasis, bacterial infections and malignant tumors. 23-hydroxybetulinic acid (23-HBA) is a pentacyclic triterpenoid extracted and isolated from its roots, and it is the main active ingredient of Pulsatilla. In plants such as RosMarinus, Opplopanax and Glycyrrhiza. [0003] 23-HBA can be regarded as a hydroxylated derivative of betulinic acid, belonging to the same lupin type triterpenoid, similar to betulinic acid, and has significant antitumor activity. Studies have shown that 23-HBA is effective against B16 (mouse melanoma cell line), SGC-7901 (human g...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61P35/00A61K31/58
CPCC07J63/008A61P35/00
Inventor 徐进宜朱华健徐盛涛刘洁鲁丽雪姚鸿陈哲生杨冬华叶文才
Owner CHINA PHARM UNIV