Betulinic acid derivative and synthesis method and application thereof

A technology of betulinic acid and its derivatives, which is applied in the field of medicine and its preparation and application, can solve the problems of low bioavailability, in vivo transmission, metabolism, poor solubility, etc., achieve good application value, make up for poor water solubility, and high yield Effect

Active Publication Date: 2018-09-21
HIGH & NEW TECH RES CENT OF HENAN ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its poor solubility in water, it leads to low bioavailability and shortcomings in in vivo transmission and metabolism.

Method used

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  • Betulinic acid derivative and synthesis method and application thereof
  • Betulinic acid derivative and synthesis method and application thereof
  • Betulinic acid derivative and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The synthesis of embodiment 1 compound xiii

[0040] The synthesis path is as follows:

[0041]

[0042] Synthesis of Compound 2: Add betulin (20.0 g, 45.2 mmol) and acetone (400 mL) into a 1000 mL three-necked flask, then add the newly prepared Jones reagent (100 mL) dropwise under ice bath, and continue the reaction for 30 Minutes later, remove the ice bath, stir at room temperature for 8 hours, add methanol (250mL) and water (250mL) to terminate the reaction, evaporate the solvent, add water, extract with ethyl acetate, combine the organic phases, dry and concentrate, and separate by column chromatography to obtain a white solid 2 (12.2 g, 26.8 mmol, 59.3%). 1 H NMR (DMSO-d 6 ,400MHz) δ: 12.08(s,1H),4.70(s,1H),4.57(s,1H),2.90~2.99(m,1H),2.46~2.30(m,2H),2.25(dt,J= 12.7, 3.5Hz, 1H), 2.15~2.08(m, 1H), 1.87~1.73(m, 3H), 1.65(s, 3H), 1.62(s, 1H), 1.54(t, J=11.3Hz, 1H ),1.48~1.00(m,15H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).

[0043]Synthesis of Co...

Embodiment 2

[0048] The synthesis of embodiment 2 compound vi

[0049] The synthetic route is as follows:

[0050]

[0051] Synthesis of Compound 2: Add betulin (20.0 g, 45.2 mmol) and acetone (400 mL) into a 1000 mL three-necked flask, then add the newly prepared Jones reagent (100 mL) dropwise under ice bath, and continue the reaction for 30 Minutes later, remove the ice bath, stir at room temperature for 8 hours, add methanol (250mL) and water (250mL) to terminate the reaction, evaporate the solvent, add water, extract with ethyl acetate, combine the organic phases, dry and concentrate, and separate by column chromatography to obtain a white solid 2 (12.2 g, 26.8 mmol, 59.3%). 1 H NMR (DMSO-d 6 ,400MHz) δ: 12.08(s,1H),4.70(s,1H),4.57(s,1H),2.90~2.99(m,1H),2.46~2.30(m,2H),2.25(dt,J= 12.7, 3.5Hz, 1H), 2.15~2.08(m, 1H), 1.87~1.73(m, 3H), 1.65(s, 3H), 1.62(s, 1H), 1.54(t, J=11.3Hz, 1H ),1.48~1.00(m,15H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).

[0052] Synthesis of Co...

Embodiment 3

[0058] The synthesis of embodiment 3 compound iv

[0059] The synthesis path is as follows:

[0060]

[0061] Synthesis of Compound 2: Add betulin (20.0 g, 45.2 mmol) and acetone (400 mL) into a 1000 mL three-necked flask, then add the newly prepared Jones reagent (100 mL) dropwise under ice bath, and continue the reaction for 30 Minutes later, remove the ice bath, stir at room temperature for 8 hours, add methanol (250mL) and water (250mL) to terminate the reaction, evaporate the solvent, add water, extract with ethyl acetate, combine the organic phases, dry and concentrate, and separate by column chromatography to obtain a white solid 2 (12.2 g, 26.8 mmol, 59.3%). 1 H NMR (DMSO-d 6 ,400MHz) δ: 12.08(s,1H),4.70(s,1H),4.57(s,1H),2.90~2.99(m,1H),2.46~2.30(m,2H),2.25(dt,J= 12.7, 3.5Hz, 1H), 2.15~2.08(m, 1H), 1.87~1.73(m, 3H), 1.65(s, 3H), 1.62(s, 1H), 1.54(t, J=11.3Hz, 1H ),1.48~1.00(m,15H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).

[0062] Synthesis of Com...

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Abstract

The invention discloses betulinic acid derivative and a synthesis method and application thereof as indicated by formula (I). The betulinic acid derivative covalently bonds with the linker 1, 2, 3-triazole at the C-2 node of the betulinic acid part contained in the betulinic acid derivative, the linker further covalently bonds with 2-fluoride-sugar nucleotides part. The compound provided by the synthesis method is to solve the low water solubility problem of betulinic acid, and bonds the betulinic acid with nucleoside compound via the stable linker 1,2,3-triazole.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a betulinic acid derivative and its synthesis method and application. Background technique [0002] Betulinic acid (BA) is a pentacyclic triterpenoid compound that exists in many plants such as birch, Prunella vulgaris, and papaya. Studies have found that betulinic acid has a wide range of physiological activities, such as anti-HIV, anti-tumor, and anti-inflammatory effects. Compared with betulinic acid, its derivatives have better activity in anti-HIV, anti-tumor, etc. For example, RPR103611 and PA457 (bevirimat) are in the clinical trial stage of anti-HIV, and NVX-207 is in the clinical trial of anti-tumor . However, due to its poor solubility in water, it leads to low bioavailability and shortcomings in in vivo transportation and metabolism. Contents of the invention [0003] The main purpose of the present invention is to ...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61P35/00A61P31/12A61P31/18A61P31/20
CPCA61P31/12A61P31/18A61P31/20A61P35/00C07J63/008
Inventor 王强李玉江郑立运郝佳王利敏刘陆平邹敏刘燕荣王璐郑果叶淑柯苗良李向力
Owner HIGH & NEW TECH RES CENT OF HENAN ACAD OF SCI
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